BACKGROUND Adaptor protein,phosphotyrosine interacting with PH domain and leucine zipper 1(APPL1)plays a crucial role in regulating insulin signaling and glucose metabolism.Mutations in the APPL1 gene have been associ...BACKGROUND Adaptor protein,phosphotyrosine interacting with PH domain and leucine zipper 1(APPL1)plays a crucial role in regulating insulin signaling and glucose metabolism.Mutations in the APPL1 gene have been associated with the development of maturity-onset diabetes of the young type 14(MODY14).Currently,only two mutations[c.1655T>A(p.Leu552*)and c.281G>A p.(Asp94Asn)]have been identified in association with this disease.Given the limited understanding of MODY14,it is imperative to identify additional cases and carry out comprehensive research on MODY14 and APPL1 mutations.AIM To assess the pathogenicity of APPL1 gene mutations in diabetic patients and to characterize the functional role of the APPL1 domain.METHODS Patients exhibiting clinical signs and a medical history suggestive of MODY were screened for the study.Whole exome sequencing was performed on the patients as well as their family members.The pathogenicity of the identified APPL1 variants was predicted on the basis of bioinformatics analysis.In addition,the pathogenicity of the novel APPL1 variant was preliminarily evaluated through in vitro functional experiments.Finally,the impact of these variants on APPL1 protein expression and the insulin pathway were assessed,and the potential mechanism underlying the interaction between the APPL1 protein and the insulin receptor was further explored.RESULTS A total of five novel mutations were identified,including four missense mutations(Asp632Tyr,Arg633His,Arg532Gln,and Ile642Met)and one intronic mutation(1153-16A>T).Pathogenicity prediction analysis revealed that the Arg532Gln was pathogenic across all predictions.The Asp632Tyr and Arg633His variants also had pathogenicity based on MutationTaster.In addition,multiple alignment of amino acid sequences showed that the Arg532Gln,Asp632Tyr,and Arg633His variants were conserved across different species.Moreover,in in vitro functional experiments,both the c.1894G>T(at Asp632Tyr)and c.1595G>A(at Arg532Gln)mutations were found to downregulate the expression of APPL1 on both protein and mRNA levels,indicating their pathogenic nature.Therefore,based on the patient’s clinical and family history,combined with the results from bioinformatics analysis and functional experiment,the c.1894G>T(at Asp632Tyr)and c.1595G>A(at Arg532Gln)mutations were classified as pathogenic mutations.Importantly,all these mutations were located within the phosphotyrosinebinding domain of APPL1,which plays a critical role in the insulin sensitization effect.CONCLUSION This study provided new insights into the pathogenicity of APPL1 gene mutations in diabetes and revealed a potential target for the diagnosis and treatment of the disease.展开更多
BACKGROUND Chronic myelomonocytic leukemia(CMML),a rare clonal hematopoietic stem cell disorder characterized by myelodysplastic syndrome and myeloproliferative neoplasms,has a generally poor prognosis,and easily prog...BACKGROUND Chronic myelomonocytic leukemia(CMML),a rare clonal hematopoietic stem cell disorder characterized by myelodysplastic syndrome and myeloproliferative neoplasms,has a generally poor prognosis,and easily progresses to acute myeloid leukemia.The simultaneous incidence of hematologic malignancies and solid tumors is extremely low,and CMML coinciding with lung malignancies is even rarer.Here,we report a case of CMML,with ASXL1 and EZH2 gene mutations,combined with non-small cell lung cancer(lung squamous cell carcinoma).CASE SUMMARY A 63-year-old male,suffering from toothache accompanied by coughing,sputum,and bloody sputum for three months,was given a blood test after experiencing continuous bleeding resulting from a tooth extraction at a local hospital.Based on morphological results,the patient was diagnosed with CMML and bronchoscopy was performed in situ to confirm the diagnosis of squamous cell carcinoma in the lower lobe of the lung.After receiving azacitidine,programmed cell death protein 1,and platinum-based chemotherapy drugs,the patient developed severe myelosuppression and eventually fatal leukocyte stasis and dyspnea.CONCLUSION During the treatment and observation of CMML and be vigilant of the growth of multiple primary malignant tumors.展开更多
BACKGROUND Cyclin-dependent kinase inhibitor 1C(CDKN1C)is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest.CDKN1C mutations can lead to IMAGe syndrome(CDKN1C al...BACKGROUND Cyclin-dependent kinase inhibitor 1C(CDKN1C)is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest.CDKN1C mutations can lead to IMAGe syndrome(CDKN1C allele gain-of-function mutations lead to intrauterine growth restriction,metaphyseal dysplasia,adrenal hypoplasia congenital,and genitourinary malformations).We present a Silver-Russell syndrome(SRS)pedigree that was due to a missense mutation affecting the same amino acid position,279,in the CDKN1C gene,resulting in the amino acid substitution p.Arg279His(c.836G>A).The affected family members had an SRS phenotype but did not have limb asymmetry or adrenal insufficiency.The amino acid changes in this specific region were located in a narrow functional region that contained mutations previously associated with IMAGe syndrome.In familial SRS patients,the PCNA region of CDKN1C should be analysed.Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.CASE SUMMARY We describe the case of an 8-year-old girl who initially presented with short stature.Her height was 91.6 cm,and her weight was 10.2 kg.Physical examination revealed that she had a relatively large head,an inverted triangular face,a protruding forehead,a low ear position,sunken eye sockets,and irregular cracked teeth but no limb asymmetry.Family history:The girl’s mother,greatgrandmother,and grandmother’s brother also had a prominent forehead,triangular face,and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency.Exome sequencing of the girl revealed a new heterozygous CDKN1C(NM_000076.2)c.836G>A mutation,resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine(p.Arg279His).The same causative mutation was found in both the proband’s mother,great-grandmother,and grandmother’s brother,who had similar phenotypes.Thus far,we found an SRS pedigree,which was due to a missense mutation affecting the same amino acid position,279,in the CDKN1C gene,resulting in the amino acid substitution p.Arg279His(c.836G>A).Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region[the proliferating cell nuclear antigen(PCNA)domain],no adrenal insufficiency was reported in this SRS pedigree.The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype.The proband was treated with recombinant human growth hormone(rhGH).After 1 year of rhGH treatment,the height standard deviation score of the proband increased by 0.93 standard deviation score,and her growth rate was 8.1 cm/year.No adverse reactions,such as abnormal blood glucose,were found.CONCLUSION Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry,and some patients may have glucose abnormalities.In familial SRS patients,the PCNA region of CDKN1C should be analysed.Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.展开更多
BACKGROUND The SETD1B gene is instrumental in human intelligence and nerve development.Mutations in the SETD1B gene have been linked in recent studies to neurodevelopmental disorders,seizures,and language delay.CASE S...BACKGROUND The SETD1B gene is instrumental in human intelligence and nerve development.Mutations in the SETD1B gene have been linked in recent studies to neurodevelopmental disorders,seizures,and language delay.CASE SUMMARY This study aimed to analyze the clinical manifestations and treatment of three patients suffering from mental retardation,epilepsy,and language delay resulting from a new mutation in the SETD1B gene.Three individuals with these symptoms were selected,and their clinical symptoms,gene test results,and treatment were analyzed.This article discusses the impact of the SETD1B gene mutation on patients and outlines the treatment approach.Among the three patients(two females and one male,aged 8,4,and 1,respectively),all exhibited psychomotor retardation,attention deficit,and hyperactivity disorder,and two had epilepsy.Antiepileptic treatment with sodium tripolyvalproate halted the seizures in the affected child,although mental development remained somewhat delayed.Whole exome sequencing revealed new mutations in the SETD1B gene for all patients,specifically with c.5473C>T(p.Arg1825trp),c.4120C>T(p.Gln1374*,593),c.14_15insC(p.His5Hisfs*33).CONCLUSION Possessing the SETD1B gene mutation may cause mental retardation accompanied by seizures and language delay.Although the exact mechanism is not fully understood,interventions such as drug therapy,rehabilitation training,and family support can assist patients in managing their symptoms and enhancing their quality of life.Furthermore,genetic testing supplies healthcare providers with more precise diagnostic and therapeutic guidance,informs families about genetic disease risks,and contributes to understanding disease pathogenesis and drug research and development.展开更多
In this editorial we comment on an article published in a recent issue of the World J Gastrointest Surg.A common gene mutation in gastric cancer(GC)is the TP53 mutation.As a tumor suppressor gene,TP53 is implicated in...In this editorial we comment on an article published in a recent issue of the World J Gastrointest Surg.A common gene mutation in gastric cancer(GC)is the TP53 mutation.As a tumor suppressor gene,TP53 is implicated in more than half of all tumor occurrences.TP53 gene mutations in GC tissue may be related with clinical pathological aspects.The TP53 mutation arose late in the progression of GC and aided in the final switch to malignancy.CDH1 encodes E-cadherin,which is involved in cell-to-cell adhesion,epithelial structure maintenance,cell polarity,differentiation,and intracellular signaling pathway modulation.CDH1 mutations and functional loss can result in diffuse GC,and CDH1 mutations can serve as independent prognostic indicators for poor prognosis.GC patients can benefit from genetic counseling and testing for CDH1 mutations.Demethylation therapy may assist to postpone the onset and progression of GC.The investigation of TP53 and CDH1 gene mutations in GC allows for the investigation of the relationship between these two gene mutations,as well as providing some basis for evaluating the prognosis of GC patients.展开更多
Steroid 5β-reductase [aldo-keto reductase family 1 member D1(AKR1D1)] is essential for bile acid biosynthesis. Bile acid deficiency caused by genetic defects in AKR1D1 leads to life-threatening neonatal hepatitis and...Steroid 5β-reductase [aldo-keto reductase family 1 member D1(AKR1D1)] is essential for bile acid biosynthesis. Bile acid deficiency caused by genetic defects in AKR1D1 leads to life-threatening neonatal hepatitis and cholestasis. There is still limited experience regarding the treatment of this disease. We describe an infant who presented with hyperbilirubinemia and coagulopathy but normal bile acid and γ-glutamyltransferase. Gene analysis was performed using genomic DNA from peripheral lymphocytes from the patient, his parents, and his elder brother. The patient was compound heterozygous for c.919C>T in exon 8 and exhibited a loss of heterozygosity of the AKR1D1 gene, which led to an amino acid substitution of arginine by cysteine at amino acid position 307(p.R307C). Based on these mutations, the patient was confirmed to have primary 5β-reductase deficiency. Ursodeoxycholic acid(UDCA) treatment did not have any effect on the patient. However, when we changed to chenodeoxycholic acid(CDCA) treatment, his symptoms and laboratory tests gradually improved. It is therefore crucial to supplement with an adequate dose of CDCA early to improve clinical symptoms and to normalize laboratory tests.展开更多
Von Meyenburg complexes(VMCs) are a rare type of ductal plate malformation. We herein report two Chinese families with VMCs, and the suspicious gene mutation of this disease. Proband A was a 62-year-old woman with abn...Von Meyenburg complexes(VMCs) are a rare type of ductal plate malformation. We herein report two Chinese families with VMCs, and the suspicious gene mutation of this disease. Proband A was a 62-year-old woman with abnormal echographic presentation of the liver. She received magnetic resonance imaging(MRI) examination and liver biopsy, and the results showed she had VMCs. Histologically proved hepatocellular carcinoma was found 1 year after the diagnosis of VMCs. Proband B was a 57-year-old woman with intrahepatic diffuselesions displayed by abdominal ultrasonography. Her final diagnoses were VMCs, congenital hepatic fibrosis, and hepatitis B surface e antigen-negative chronic hepatitis B after a series of examinations. Then, all the family members of both proband A and proband B were screened for VMCs by MRI or ultrasonography. The results showed that four of the 11 family members from two families, including two males and two females, were diagnosed with VMCs. DNA samples were extracted from the peripheral blood of those 11 individuals of two VMCs pedigrees and subjected to polymerase chain reaction amplification of the polycystic kidney and hepatic disease 1(PKHD1) gene. Two different mutation loci were identified. Heterozygous mutations located in exon 32(c.4280 delG, p.Gly1427 ValfsX 6) in family A and exon 28(c.3118 C>T, p.Arg1040 Ter) in family B were detected. We speculate that PKHD1 gene mutations may be responsible for the development of VMCs.展开更多
The influenza A viruses have three gene segments, M, NS, and PB1, which code for more than one protein. The overlapping genes from the same segment entail their interdependence, which could be reflected in the evoluti...The influenza A viruses have three gene segments, M, NS, and PB1, which code for more than one protein. The overlapping genes from the same segment entail their interdependence, which could be reflected in the evolutionary constraints, host distinction, and co-mutations of influenza. Most previous studies of overlapping genes focused on their unique evolutionary constraints, and very little was achieved to assess the potential impact of the overlap on other biological aspects of influenza. In this study, our aim was to explore the mutual dependence in host differentiation and co-mutations in M, NS, and PB1 of avian, human, 2009 H1N1, and swine viruses, with Random Forests, information entropy, and mutual information. The host markers and highly co-mutated individual sites and site pairs (P values < 0.035) in the three gene segments were identified with their relative significance between the overlapping genes calculated. Further, Random Forests predicted that among the three stop codons in the current PB1-F2 gene of 2009 H1N1, the significance of a mutation at these sites for host differentiation was, in order from most to least, that at 12, 58, and 88, i.e., the closer to the start of the gene the more important the mutation was. Finally, our sequence analysis surprisingly revealed that the full-length PB1-F2, if the three stop codons were all mutated, would function more as a swine protein than a human protein, although the PB1 of 2009 H1N1 was derived from human H3N2.展开更多
AIM:To screen mutations in the retinitis pigmentosa 1(RP1) gene and the rhodopsin(RHO) gene in Chinese patients with retinitis pigmentosa sine pigmento(RPSP)and describe the genotype-phenotype relationship of the muta...AIM:To screen mutations in the retinitis pigmentosa 1(RP1) gene and the rhodopsin(RHO) gene in Chinese patients with retinitis pigmentosa sine pigmento(RPSP)and describe the genotype-phenotype relationship of the mutations.·METHODS:Twenty affected,unrelated Chinese individuals with RPSP(4 autosomal dominant RPSP,12autosomal recessive RPSP and 4 unknown inheritance pattern) were recruited between 2009 and 2012.The clinical features were determined by complete ophthalmologic examinations.Polymerase chain reaction(PCR) and direct DNA sequencing were used to screen the entire coding region and splice junctions of the RP1gene and the RHO gene.The cosegregation analysis and population frequency studies were performed for patients with identified mutations.·RESULTS:Five variants in the RP1 gene and one in the RHO gene were detected in 20 probands.Four missense changes(rs444772,rs446227,rs414352,rs441800) and one non-coding variant(rs56340615) were common SNPs and none of them showed a significant relationship with RPSP.A missense mutation p.R1443W was identified in the RP1 gene in three affected individuals from a family with autosomal dominant RPSP and was found to cosegregate with the phenotype in this family,suggestive of pathogenic.In addition,population frequency analysis showed the p.R1443W mutation was absent in 300 healthy controls.·CONCLUSION:The identification of p.R1443W mutationcosegregating in a family with autosomal dominant RPSP highlights an atypical phenotype of the RP1 gene mutation,while RHO gene is not associated with the pathogenesis of RPSP in this study.To our knowledge,this is the fist mutation identified to associate with RPSP.展开更多
AIM: To identify the mutations in RS1 gene associated with typical phenotype of X-linked juvenile retinoschisis(XLRS) and a rare condition of concomitant glaucoma. ·METHODS: Complete ophthalmic examinations were ...AIM: To identify the mutations in RS1 gene associated with typical phenotype of X-linked juvenile retinoschisis(XLRS) and a rare condition of concomitant glaucoma. ·METHODS: Complete ophthalmic examinations were performed in the proband. The coding regions of the RS1 gene that encode retinoschisin were amplified by polymerase chain reaction and directly sequenced. ·RESULTS: The proband showed a typical phenotype of XLRS with large peripheral retinal schisis in both eyes,involving the macula and combined with foveal cystic change,reducing visual acuity. A typical phenotype of recurrent glaucoma with high intraocular pressure(IOP) and reduced visual field was also demonstrated with the patient. Mutation analysis of RS1 gene revealed R102W(c.304C>T) mutations in the affected male,and his mother was proved to be a carrier with the causative mutation and another synonymous polymorphism(c.576C>CT). ·CONCLUSION: We identified the genetic variations of a Chinese family with typical phenotype of XLRS and glaucoma. The severe XLRS phenotypes associated with R102W mutations reveal that the mutation determines a notable alteration in the function of the retinoschisin protein. Identification of the disease-causing mutation is beneficial for future clinical references.展开更多
AIM: To identify the novel mutation alleles in the CYP1B1 gene of primary congenital glaucoma(PCG) patients at Shandong Province of China, and investigate their correlation with glaucomatous features.METHODS: The DNA ...AIM: To identify the novel mutation alleles in the CYP1B1 gene of primary congenital glaucoma(PCG) patients at Shandong Province of China, and investigate their correlation with glaucomatous features.METHODS: The DNA from the peripheral blood of 13 congenital glaucoma patients and 50 ethnically matched healthy controls from the affiliated hospital of Qingdao University were extracted. The coding region of the CYP1B1 gene was amplified by PCR and direct DNA sequencing was performed. Disease causing-variants were analyzed by comparing the sequences and the structures of wild type and mutant CYP1B1 proteins by PyMOL software.RESULTS: Two missense mutations, including A330 F caused by c.988 G>T&c.989 C>T, and R390H caused by c.1169 G>A, were identified in one of the 13 PCG patients analyzed in our study. A330F mutation was observed to be novel in the Chinese Han population, which dramatically altered the protein structure of CYP1B1 gene, including the changes in the ligand-binding pocket. Furthermore, R390H mutation caused the changes in heme-protein binding site of this gene. In addition, the clinical phenotype displayed by PCG patient with these mutations was more pronounced than other PCG patients without these mutations. Multiple surgeries and combined drug treatment were not effective in reducing the elevated intraocular pressure in this patient.CONCLUSION: A novel A330F mutation is identified in the CYP1B1 gene of Chinese PCG patient. Moreover, in combination with other mutation R390H, this PCG patient shows significant difference in the CYP1B1 protein structure, which may specifically contribute to severe glaucomatous phenotype.展开更多
BACKGROUND The VPS33B(OMIM:608552)gene is located on chromosome 15q26.1.We found a female infant with autosomal recessive arthrogryposis,renal dysfunction and cholestasis syndrome 1(ARCS1)caused by mutation in VPS33B....BACKGROUND The VPS33B(OMIM:608552)gene is located on chromosome 15q26.1.We found a female infant with autosomal recessive arthrogryposis,renal dysfunction and cholestasis syndrome 1(ARCS1)caused by mutation in VPS33B.The child was diagnosed with ARCS1(OMIM:208085)after the whole exome sequencing revealed two heterozygous mutations(c.96+1G>C,c.242delT)in the VPS33B gene.CASE SUMMARY We report a Chinese female infant with neonatal cholestasis disorder,who was eventually diagnosed with ARCS1 by genetic analysis.Genetic testing revealed two new mutations(c.96+1G>C and c.242delT)in VPS33B,which is the causal gene.The patient was compound heterozygous,and her parents were both heterozygous.CONCLUSION This study extends the mutational spectrum of the VPS33B gene to provide a molecular basis for the etiological diagnosis of ARCS1 and for genetic counseling of the family.展开更多
AIM: To investigate the association of serum glucocorticoid kinase gene-1(SGK-1) DNA variants with chronic central serous chorioretinopathy(CSC).METHODS: We enrolled 32 eyes of 32 patients who were diagnosed with chro...AIM: To investigate the association of serum glucocorticoid kinase gene-1(SGK-1) DNA variants with chronic central serous chorioretinopathy(CSC).METHODS: We enrolled 32 eyes of 32 patients who were diagnosed with chronic CSC and composed 32 normal eyes as a control group. Peripheral blood was used for DNA extraction and polymerase chain reaction amplification. SGK1 gene was sequenced by using Big Dye Terminator v3.1 cycle sequencing Kit(Applied Biosystems, Foster City, CA, USA). The SGK-1 gene and its variants were investigated in CSC patient group and control group.RESULTS: We identified a new polymorphism M32 V in two person in the patient group [Minor allele frequency(MAF) =0.009] on the region of 1-60 amino acids. The rs1057293 was located in the encoder region of the SGK- 1 gene but not associated with CSC(P =0.68). An intrinsic rs1743966 is also not associated(P =0.28).CONCLUSION: The new polymorphism M32 V is located on the region of 1-60 amino acids which is necessary for localization to the mitochondria in CSC patient. This mutation is probably important for the energy metabolism and plays an important role in the cellular response to hyperosmotic stress and other stress stimuli. Both rs1057293 and rs1743966 are not associated with CSC.展开更多
Background and Objective Marfan syndrome,a variable and heritable disorder of fibrous connective tissue,characterized by affecting skeletal,ocular and cardiovascular systems.With the research advancement of genetic me...Background and Objective Marfan syndrome,a variable and heritable disorder of fibrous connective tissue,characterized by affecting skeletal,ocular and cardiovascular systems.With the research advancement of genetic mechanism,the diagnosis of Marfan syndrome,based on clinical manifestations and genetic evidence,is more accurate.The aim of this study is identification of genetic pathogenesis in a Chinese family.展开更多
AIM:To describe the clinical heterogeneity of patients with novel mutations in BEST1.METHODS:All the members in the two Chinese families underwent detailed clinical evaluations including best-corrected visual acuity,s...AIM:To describe the clinical heterogeneity of patients with novel mutations in BEST1.METHODS:All the members in the two Chinese families underwent detailed clinical evaluations including best-corrected visual acuity,slit-lamp examination,applanation tonometry,and dilated fundus examination.Fundus autofluorescence,fundus fluorescein angiography,spectral-domain optical coherence tomography,electrooculography,and electroretinogram were also performed.Genomic DNA was extracted from venous blood for all the participants.The targeted next-generation sequencing of inherited retinal disease-associated genes was conducted to identify the causative mutation.RESULTS:A novel BEST1 missense mutation c.41T>C(p.Leu14Ser) was identified in Family 1.It was co-segregated with the phenotype of best vitelliform macular dystrophy(BVMD) and bioinformatics analysis confirmed it was harmful.Another novel BEST1 frameshift mutation c.345_(3)46insGGCAAGGACG(p.Glu119Glyfs*116) and a novel USH2A missense mutation c.12560G>A,p.Arg4187 His were identified in family 2 with retinitis pigmentosa(RP),which might interact and lead to the phenotype of RP.CONCLUSION:Two novel mutations in the BEST1 gene in two unrelated families with distinct phenotypes and BEST1 mutation accompanied with USH2A mutation would result in RP,which could be enormously helpful in understanding the pathogenesis of the inherited retinal disease caused by a BEST1 mutation.展开更多
BACKGROUND Approximately 10%of adults and nearly all children who receive renal replacement therapy have inherited risk factors or are related to genetic factors.In the past,due to the limitations of detection technol...BACKGROUND Approximately 10%of adults and nearly all children who receive renal replacement therapy have inherited risk factors or are related to genetic factors.In the past,due to the limitations of detection technology and the nonspecific manifestations of uraemia,the etiological diagnosis is unclear.In addition to common monogenic diseases and complex disorders,advanced testing techniques have led to the recognition of more hereditary renal diseases.Here,we report a four-generation Chinese family in which four individuals had a novel SALL1 mutation and presented with uraemia or abnormal urine tests.CASE SUMMARY A 32-year-old man presented with end-stage renal disease with a 4-year history of dialysis.His father and paternal aunt both had a history of unexplained renal failure with haemodialysis,and his 10-year-old daughter presented with proteinuria.The patient had multiple congenital abnormalities,including bilateral overlapping toes,unilateral dysplastic external ears,and sensorineural hearing loss.His family members also presented with similar defects.Genetic testing revealed that the proband carried a novel heterozygous shift mutation in SALL1_exon 2(c.3437delG),and Sanger sequencing confirmed the same mutation in all affected family members.CONCLUSION We report a novel SALL1 exon 2(c.3437delG)mutation and clinical syndrome with kidney disease,bilateral overlapping toes,unilateral dysplastic external ears,and sensorineural hearing loss in a four-generation Chinese family.展开更多
<strong>Background:</strong><span><span style="font-family:Verdana;"> Dental complications of Ehlers-Danlos syndrome (EDS) include periodontitis with gum fragility and inflammation, e...<strong>Background:</strong><span><span style="font-family:Verdana;"> Dental complications of Ehlers-Danlos syndrome (EDS) include periodontitis with gum fragility and inflammation, enamel hypoplasia with frequent caries, high palate with dental crowding, TMJ instability, sutur</span><span><span style="font-family:Verdana;">al dehiscence or scarring, and insensitivity to anesthetics. </span><b><span style="font-family:Verdana;">Objective:</span></b><span style="font-family:Verdana;"> Determine if EDS dental complications always define a specific type and genetic cause or if they can arise as a general consequence of altered inflammatory response in EDS. </span><b><span style="font-family:Verdana;">Method:</span></b><span style="font-family:Verdana;"> We compared findings of a 58-year-old female</span></span><span style="font-family:Verdana;"> with complement component 1R (C1R</span><span style="font-family:Verdana;">) </span><span style="font-family:Verdana;">gene mutation (c.1553A > T, p.Asp518Val) </span><span><span style="font-family:Verdana;">found by whole exome sequencing to 43 patients with C1R gene mutations ascertained because of periodontal disease and to 710 EDS patients conventially ascertained because of joint and skin laxity. </span><b><span style="font-family:Verdana;">Result:</span></b><span style="font-family:Verdana;"> Female patients ascertained as periodontal EDS showed the expected higher frequency of periodontitis (96% versus 14%) but had similar frequencies of hypermobility (81% versus 90%) and some skin findings (84% versus 92% with skin fragility) as the general group and our female patient who shared their </span><span style="font-family:Verdana;">C1R</span><span style="font-family:Verdana;"> gene change. Her oromandibular bone loss rather than gum dis</span></span><span><span style="font-family:Verdana;">ease may reflect the more carboxy-terminal position of her </span><span style="font-family:Verdana;"><span style="font-family:Verdana;">C</span></span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">1</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">R</span></span></span><span><span><span> </span></span></span><span style="font-family:Verdana;">gene mutatio</span><span><span style="font-family:Verdana;">n compared to those in the patients identified as periodontal EDS. </span><b><span style="font-family:Verdana;">Conclusion:</span></b> <span><span style="font-family:Verdana;">While mutation of the </span><span style="font-family:Verdana;">C1R </span><span style="font-family:Verdana;">gene may predict more frequent periodontal, skin, and vascular complications, focus on an articulo-autonomic dysplasia process that includes mast-cell activation and altered inflammatory response rather than extreme EDS types will help dentists and other subspecialists identify all EDS patients and anticipate their frequent oral manifestations.</span></span></span>展开更多
AIM: To verify and expand the known spectrum of serine protease inhibitor Kazal type 1 (SPINK1) gene mutations in chronic pancreatitis. METHODS: DNA extracted from 172 chronic pancreatitis patients was assayed for SPI...AIM: To verify and expand the known spectrum of serine protease inhibitor Kazal type 1 (SPINK1) gene mutations in chronic pancreatitis. METHODS: DNA extracted from 172 chronic pancreatitis patients was assayed for SPINK1 gene mutations by PCR and DNA sequencing. A control cohort of 90 unrelated healthy individuals was analysed by the same methods for presence of common populational polymorphisms, and frequency of five-loci haplotypes was calculated. Linkages of gene aberrations in single SPINK1 gene copies were analysed by long-distance PCR followed by allele-specifi c PCR and DNA sequencing. RESULTS: The most frequent SPINK1 gene mutation N34S was found at a frequency of 6%. Furthermore, we detected the heterozygous intervening sequence (IVS) 3 + 2 T > C mutated gene in 2 German patients and 1 Macedonian chronic pancreatitis patient. In all three SPINK1 gene copies an additional rare base substitution was found: 5’untranslated region (UTR)-215 G > A. Poly-morphism analysis revealed that all three affected genes carried the same fi ve-loci haplotype. DNA sequencing of another chronic pancreatitis-related gene PRSS1 (cationic trypsinogen) did not reveal any mutations in these 3 pa-tients.CONCLUSION: We found in 3 (2%) of 172 chronic pancreatitis patients an IVS3 + 2 T > C SPINK1 gene mutation and a base substitution 5’UTR-215 G > A inthe same gene copy. Most probably the 5’UTR-215 G >A represents a rare polymorphism and not a mutationas previously concluded. Haplotype analysis suggests acommon origin of the IVS3 + 2 T > C mutation in thesepatients.展开更多
Abstract Objective:To establish a reformative detection system which has sound ability of providing infor-mation on molecular mutagenesis spectrum and the specificity of detection system of repackaged λ phage.Methods...Abstract Objective:To establish a reformative detection system which has sound ability of providing infor-mation on molecular mutagenesis spectrum and the specificity of detection system of repackaged λ phage.Methods:LacZ gene,as mutational target gene and reporter gene, was applied into the detection system.The λ gt11 DNA treated with ENU(1-ethyl-1-nitrosourea)and 9-AA(9-aminoacridine)was repackaged in vitro.The packaged λ phage was then grown in E.coli Y1090 on a selective plate containing X-gel and IPTG.The survival and mutation frequencies were determined by counting the clear-plaque and blue-plaque,and the molecular mutation mechanism was studied by extracting and sequencing the LacZ gene of mutants.Results:The survival of repackaged λ phages treated with 9-AA and ENU apparently decreased in consistent dose-dependence.The mutation frequency of clear-plaque mutants showed a linear dose-related increase.The predominant mutations induced by 9-AA were ±1 frameshift mutation, and 9-AA induced -1 frameshift was much more effective than induced +1 frameshift.9-AA also induced substitutions with transversions more common.ENU -induced mutations were chiefly occurred at G:C sites .Substitutions induced by ENU were mainly G:C→A:T,G:C→C:Gand A:T→T:A transversion.Conclusion;Mutation detection sys-tem of λgt 11 DNA containing LacZ gene is proven better than that of λDNA without LacZ gene.The combi-nation of survival, mutant frequency and sequence spectrum can not only increase the sensitivity and specifici-ty of the new method, but also provide a better understanding of the molecular mechanism of mutation for ul-timate extrapolation to risk assessment.展开更多
基金Supported by the National Natural Science Foundation,No.81974124and Taishan Scholar Project,No.tsqn20161071.
文摘BACKGROUND Adaptor protein,phosphotyrosine interacting with PH domain and leucine zipper 1(APPL1)plays a crucial role in regulating insulin signaling and glucose metabolism.Mutations in the APPL1 gene have been associated with the development of maturity-onset diabetes of the young type 14(MODY14).Currently,only two mutations[c.1655T>A(p.Leu552*)and c.281G>A p.(Asp94Asn)]have been identified in association with this disease.Given the limited understanding of MODY14,it is imperative to identify additional cases and carry out comprehensive research on MODY14 and APPL1 mutations.AIM To assess the pathogenicity of APPL1 gene mutations in diabetic patients and to characterize the functional role of the APPL1 domain.METHODS Patients exhibiting clinical signs and a medical history suggestive of MODY were screened for the study.Whole exome sequencing was performed on the patients as well as their family members.The pathogenicity of the identified APPL1 variants was predicted on the basis of bioinformatics analysis.In addition,the pathogenicity of the novel APPL1 variant was preliminarily evaluated through in vitro functional experiments.Finally,the impact of these variants on APPL1 protein expression and the insulin pathway were assessed,and the potential mechanism underlying the interaction between the APPL1 protein and the insulin receptor was further explored.RESULTS A total of five novel mutations were identified,including four missense mutations(Asp632Tyr,Arg633His,Arg532Gln,and Ile642Met)and one intronic mutation(1153-16A>T).Pathogenicity prediction analysis revealed that the Arg532Gln was pathogenic across all predictions.The Asp632Tyr and Arg633His variants also had pathogenicity based on MutationTaster.In addition,multiple alignment of amino acid sequences showed that the Arg532Gln,Asp632Tyr,and Arg633His variants were conserved across different species.Moreover,in in vitro functional experiments,both the c.1894G>T(at Asp632Tyr)and c.1595G>A(at Arg532Gln)mutations were found to downregulate the expression of APPL1 on both protein and mRNA levels,indicating their pathogenic nature.Therefore,based on the patient’s clinical and family history,combined with the results from bioinformatics analysis and functional experiment,the c.1894G>T(at Asp632Tyr)and c.1595G>A(at Arg532Gln)mutations were classified as pathogenic mutations.Importantly,all these mutations were located within the phosphotyrosinebinding domain of APPL1,which plays a critical role in the insulin sensitization effect.CONCLUSION This study provided new insights into the pathogenicity of APPL1 gene mutations in diabetes and revealed a potential target for the diagnosis and treatment of the disease.
文摘BACKGROUND Chronic myelomonocytic leukemia(CMML),a rare clonal hematopoietic stem cell disorder characterized by myelodysplastic syndrome and myeloproliferative neoplasms,has a generally poor prognosis,and easily progresses to acute myeloid leukemia.The simultaneous incidence of hematologic malignancies and solid tumors is extremely low,and CMML coinciding with lung malignancies is even rarer.Here,we report a case of CMML,with ASXL1 and EZH2 gene mutations,combined with non-small cell lung cancer(lung squamous cell carcinoma).CASE SUMMARY A 63-year-old male,suffering from toothache accompanied by coughing,sputum,and bloody sputum for three months,was given a blood test after experiencing continuous bleeding resulting from a tooth extraction at a local hospital.Based on morphological results,the patient was diagnosed with CMML and bronchoscopy was performed in situ to confirm the diagnosis of squamous cell carcinoma in the lower lobe of the lung.After receiving azacitidine,programmed cell death protein 1,and platinum-based chemotherapy drugs,the patient developed severe myelosuppression and eventually fatal leukocyte stasis and dyspnea.CONCLUSION During the treatment and observation of CMML and be vigilant of the growth of multiple primary malignant tumors.
基金Supported by the China Foundation for International Medical Exchange,Pediatric Endocrinology Young and Middle-Aged Doctors’Growth Research Fund,No.Z-2019-41-2101-01.
文摘BACKGROUND Cyclin-dependent kinase inhibitor 1C(CDKN1C)is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest.CDKN1C mutations can lead to IMAGe syndrome(CDKN1C allele gain-of-function mutations lead to intrauterine growth restriction,metaphyseal dysplasia,adrenal hypoplasia congenital,and genitourinary malformations).We present a Silver-Russell syndrome(SRS)pedigree that was due to a missense mutation affecting the same amino acid position,279,in the CDKN1C gene,resulting in the amino acid substitution p.Arg279His(c.836G>A).The affected family members had an SRS phenotype but did not have limb asymmetry or adrenal insufficiency.The amino acid changes in this specific region were located in a narrow functional region that contained mutations previously associated with IMAGe syndrome.In familial SRS patients,the PCNA region of CDKN1C should be analysed.Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.CASE SUMMARY We describe the case of an 8-year-old girl who initially presented with short stature.Her height was 91.6 cm,and her weight was 10.2 kg.Physical examination revealed that she had a relatively large head,an inverted triangular face,a protruding forehead,a low ear position,sunken eye sockets,and irregular cracked teeth but no limb asymmetry.Family history:The girl’s mother,greatgrandmother,and grandmother’s brother also had a prominent forehead,triangular face,and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency.Exome sequencing of the girl revealed a new heterozygous CDKN1C(NM_000076.2)c.836G>A mutation,resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine(p.Arg279His).The same causative mutation was found in both the proband’s mother,great-grandmother,and grandmother’s brother,who had similar phenotypes.Thus far,we found an SRS pedigree,which was due to a missense mutation affecting the same amino acid position,279,in the CDKN1C gene,resulting in the amino acid substitution p.Arg279His(c.836G>A).Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region[the proliferating cell nuclear antigen(PCNA)domain],no adrenal insufficiency was reported in this SRS pedigree.The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype.The proband was treated with recombinant human growth hormone(rhGH).After 1 year of rhGH treatment,the height standard deviation score of the proband increased by 0.93 standard deviation score,and her growth rate was 8.1 cm/year.No adverse reactions,such as abnormal blood glucose,were found.CONCLUSION Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry,and some patients may have glucose abnormalities.In familial SRS patients,the PCNA region of CDKN1C should be analysed.Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.
基金Key Health Science and Technology Development Project of Nanjing City,Jiangsu Province,No.ZKX19038.
文摘BACKGROUND The SETD1B gene is instrumental in human intelligence and nerve development.Mutations in the SETD1B gene have been linked in recent studies to neurodevelopmental disorders,seizures,and language delay.CASE SUMMARY This study aimed to analyze the clinical manifestations and treatment of three patients suffering from mental retardation,epilepsy,and language delay resulting from a new mutation in the SETD1B gene.Three individuals with these symptoms were selected,and their clinical symptoms,gene test results,and treatment were analyzed.This article discusses the impact of the SETD1B gene mutation on patients and outlines the treatment approach.Among the three patients(two females and one male,aged 8,4,and 1,respectively),all exhibited psychomotor retardation,attention deficit,and hyperactivity disorder,and two had epilepsy.Antiepileptic treatment with sodium tripolyvalproate halted the seizures in the affected child,although mental development remained somewhat delayed.Whole exome sequencing revealed new mutations in the SETD1B gene for all patients,specifically with c.5473C>T(p.Arg1825trp),c.4120C>T(p.Gln1374*,593),c.14_15insC(p.His5Hisfs*33).CONCLUSION Possessing the SETD1B gene mutation may cause mental retardation accompanied by seizures and language delay.Although the exact mechanism is not fully understood,interventions such as drug therapy,rehabilitation training,and family support can assist patients in managing their symptoms and enhancing their quality of life.Furthermore,genetic testing supplies healthcare providers with more precise diagnostic and therapeutic guidance,informs families about genetic disease risks,and contributes to understanding disease pathogenesis and drug research and development.
基金Supported by the Youth Development Fund Task Book of the First Hospital of Jilin University,No.JDYY13202210.
文摘In this editorial we comment on an article published in a recent issue of the World J Gastrointest Surg.A common gene mutation in gastric cancer(GC)is the TP53 mutation.As a tumor suppressor gene,TP53 is implicated in more than half of all tumor occurrences.TP53 gene mutations in GC tissue may be related with clinical pathological aspects.The TP53 mutation arose late in the progression of GC and aided in the final switch to malignancy.CDH1 encodes E-cadherin,which is involved in cell-to-cell adhesion,epithelial structure maintenance,cell polarity,differentiation,and intracellular signaling pathway modulation.CDH1 mutations and functional loss can result in diffuse GC,and CDH1 mutations can serve as independent prognostic indicators for poor prognosis.GC patients can benefit from genetic counseling and testing for CDH1 mutations.Demethylation therapy may assist to postpone the onset and progression of GC.The investigation of TP53 and CDH1 gene mutations in GC allows for the investigation of the relationship between these two gene mutations,as well as providing some basis for evaluating the prognosis of GC patients.
基金the Guangdong Medical Research Foundation,No.A2018550
文摘Steroid 5β-reductase [aldo-keto reductase family 1 member D1(AKR1D1)] is essential for bile acid biosynthesis. Bile acid deficiency caused by genetic defects in AKR1D1 leads to life-threatening neonatal hepatitis and cholestasis. There is still limited experience regarding the treatment of this disease. We describe an infant who presented with hyperbilirubinemia and coagulopathy but normal bile acid and γ-glutamyltransferase. Gene analysis was performed using genomic DNA from peripheral lymphocytes from the patient, his parents, and his elder brother. The patient was compound heterozygous for c.919C>T in exon 8 and exhibited a loss of heterozygosity of the AKR1D1 gene, which led to an amino acid substitution of arginine by cysteine at amino acid position 307(p.R307C). Based on these mutations, the patient was confirmed to have primary 5β-reductase deficiency. Ursodeoxycholic acid(UDCA) treatment did not have any effect on the patient. However, when we changed to chenodeoxycholic acid(CDCA) treatment, his symptoms and laboratory tests gradually improved. It is therefore crucial to supplement with an adequate dose of CDCA early to improve clinical symptoms and to normalize laboratory tests.
基金Supported by Pilot Project of Fujian Science and Technology Department,No.2015Y0057Fujian Medical Innovation Project,No.2018-ZQN-54Science and Technology Project of Fujian Education Department,No.JAT160211
文摘Von Meyenburg complexes(VMCs) are a rare type of ductal plate malformation. We herein report two Chinese families with VMCs, and the suspicious gene mutation of this disease. Proband A was a 62-year-old woman with abnormal echographic presentation of the liver. She received magnetic resonance imaging(MRI) examination and liver biopsy, and the results showed she had VMCs. Histologically proved hepatocellular carcinoma was found 1 year after the diagnosis of VMCs. Proband B was a 57-year-old woman with intrahepatic diffuselesions displayed by abdominal ultrasonography. Her final diagnoses were VMCs, congenital hepatic fibrosis, and hepatitis B surface e antigen-negative chronic hepatitis B after a series of examinations. Then, all the family members of both proband A and proband B were screened for VMCs by MRI or ultrasonography. The results showed that four of the 11 family members from two families, including two males and two females, were diagnosed with VMCs. DNA samples were extracted from the peripheral blood of those 11 individuals of two VMCs pedigrees and subjected to polymerase chain reaction amplification of the polycystic kidney and hepatic disease 1(PKHD1) gene. Two different mutation loci were identified. Heterozygous mutations located in exon 32(c.4280 delG, p.Gly1427 ValfsX 6) in family A and exon 28(c.3118 C>T, p.Arg1040 Ter) in family B were detected. We speculate that PKHD1 gene mutations may be responsible for the development of VMCs.
文摘The influenza A viruses have three gene segments, M, NS, and PB1, which code for more than one protein. The overlapping genes from the same segment entail their interdependence, which could be reflected in the evolutionary constraints, host distinction, and co-mutations of influenza. Most previous studies of overlapping genes focused on their unique evolutionary constraints, and very little was achieved to assess the potential impact of the overlap on other biological aspects of influenza. In this study, our aim was to explore the mutual dependence in host differentiation and co-mutations in M, NS, and PB1 of avian, human, 2009 H1N1, and swine viruses, with Random Forests, information entropy, and mutual information. The host markers and highly co-mutated individual sites and site pairs (P values < 0.035) in the three gene segments were identified with their relative significance between the overlapping genes calculated. Further, Random Forests predicted that among the three stop codons in the current PB1-F2 gene of 2009 H1N1, the significance of a mutation at these sites for host differentiation was, in order from most to least, that at 12, 58, and 88, i.e., the closer to the start of the gene the more important the mutation was. Finally, our sequence analysis surprisingly revealed that the full-length PB1-F2, if the three stop codons were all mutated, would function more as a swine protein than a human protein, although the PB1 of 2009 H1N1 was derived from human H3N2.
基金Ningxia Scientific and Technological Projects from Department of Science and Technology in Ningxia Hui Autonomous Region (No.2011ZYS175)
文摘AIM:To screen mutations in the retinitis pigmentosa 1(RP1) gene and the rhodopsin(RHO) gene in Chinese patients with retinitis pigmentosa sine pigmento(RPSP)and describe the genotype-phenotype relationship of the mutations.·METHODS:Twenty affected,unrelated Chinese individuals with RPSP(4 autosomal dominant RPSP,12autosomal recessive RPSP and 4 unknown inheritance pattern) were recruited between 2009 and 2012.The clinical features were determined by complete ophthalmologic examinations.Polymerase chain reaction(PCR) and direct DNA sequencing were used to screen the entire coding region and splice junctions of the RP1gene and the RHO gene.The cosegregation analysis and population frequency studies were performed for patients with identified mutations.·RESULTS:Five variants in the RP1 gene and one in the RHO gene were detected in 20 probands.Four missense changes(rs444772,rs446227,rs414352,rs441800) and one non-coding variant(rs56340615) were common SNPs and none of them showed a significant relationship with RPSP.A missense mutation p.R1443W was identified in the RP1 gene in three affected individuals from a family with autosomal dominant RPSP and was found to cosegregate with the phenotype in this family,suggestive of pathogenic.In addition,population frequency analysis showed the p.R1443W mutation was absent in 300 healthy controls.·CONCLUSION:The identification of p.R1443W mutationcosegregating in a family with autosomal dominant RPSP highlights an atypical phenotype of the RP1 gene mutation,while RHO gene is not associated with the pathogenesis of RPSP in this study.To our knowledge,this is the fist mutation identified to associate with RPSP.
基金Supported by the National Key Basic Research Program(2013CB967502,2013CB967503)Most Major Projects(2012YQ12008004)+1 种基金Qianjiang Talents Project(2012R10072)Zhejiang Provincial Natural Science Foundation of China(No.LR13H120001)
文摘AIM: To identify the mutations in RS1 gene associated with typical phenotype of X-linked juvenile retinoschisis(XLRS) and a rare condition of concomitant glaucoma. ·METHODS: Complete ophthalmic examinations were performed in the proband. The coding regions of the RS1 gene that encode retinoschisin were amplified by polymerase chain reaction and directly sequenced. ·RESULTS: The proband showed a typical phenotype of XLRS with large peripheral retinal schisis in both eyes,involving the macula and combined with foveal cystic change,reducing visual acuity. A typical phenotype of recurrent glaucoma with high intraocular pressure(IOP) and reduced visual field was also demonstrated with the patient. Mutation analysis of RS1 gene revealed R102W(c.304C>T) mutations in the affected male,and his mother was proved to be a carrier with the causative mutation and another synonymous polymorphism(c.576C>CT). ·CONCLUSION: We identified the genetic variations of a Chinese family with typical phenotype of XLRS and glaucoma. The severe XLRS phenotypes associated with R102W mutations reveal that the mutation determines a notable alteration in the function of the retinoschisin protein. Identification of the disease-causing mutation is beneficial for future clinical references.
基金Supported by “Clinical medical+X” Project from Department of Medicine of Qingdao University
文摘AIM: To identify the novel mutation alleles in the CYP1B1 gene of primary congenital glaucoma(PCG) patients at Shandong Province of China, and investigate their correlation with glaucomatous features.METHODS: The DNA from the peripheral blood of 13 congenital glaucoma patients and 50 ethnically matched healthy controls from the affiliated hospital of Qingdao University were extracted. The coding region of the CYP1B1 gene was amplified by PCR and direct DNA sequencing was performed. Disease causing-variants were analyzed by comparing the sequences and the structures of wild type and mutant CYP1B1 proteins by PyMOL software.RESULTS: Two missense mutations, including A330 F caused by c.988 G>T&c.989 C>T, and R390H caused by c.1169 G>A, were identified in one of the 13 PCG patients analyzed in our study. A330F mutation was observed to be novel in the Chinese Han population, which dramatically altered the protein structure of CYP1B1 gene, including the changes in the ligand-binding pocket. Furthermore, R390H mutation caused the changes in heme-protein binding site of this gene. In addition, the clinical phenotype displayed by PCG patient with these mutations was more pronounced than other PCG patients without these mutations. Multiple surgeries and combined drug treatment were not effective in reducing the elevated intraocular pressure in this patient.CONCLUSION: A novel A330F mutation is identified in the CYP1B1 gene of Chinese PCG patient. Moreover, in combination with other mutation R390H, this PCG patient shows significant difference in the CYP1B1 protein structure, which may specifically contribute to severe glaucomatous phenotype.
基金Supported by the Hainan Province Clinical Medical Center,No.(2021)75 and(2021)276。
文摘BACKGROUND The VPS33B(OMIM:608552)gene is located on chromosome 15q26.1.We found a female infant with autosomal recessive arthrogryposis,renal dysfunction and cholestasis syndrome 1(ARCS1)caused by mutation in VPS33B.The child was diagnosed with ARCS1(OMIM:208085)after the whole exome sequencing revealed two heterozygous mutations(c.96+1G>C,c.242delT)in the VPS33B gene.CASE SUMMARY We report a Chinese female infant with neonatal cholestasis disorder,who was eventually diagnosed with ARCS1 by genetic analysis.Genetic testing revealed two new mutations(c.96+1G>C and c.242delT)in VPS33B,which is the causal gene.The patient was compound heterozygous,and her parents were both heterozygous.CONCLUSION This study extends the mutational spectrum of the VPS33B gene to provide a molecular basis for the etiological diagnosis of ARCS1 and for genetic counseling of the family.
文摘AIM: To investigate the association of serum glucocorticoid kinase gene-1(SGK-1) DNA variants with chronic central serous chorioretinopathy(CSC).METHODS: We enrolled 32 eyes of 32 patients who were diagnosed with chronic CSC and composed 32 normal eyes as a control group. Peripheral blood was used for DNA extraction and polymerase chain reaction amplification. SGK1 gene was sequenced by using Big Dye Terminator v3.1 cycle sequencing Kit(Applied Biosystems, Foster City, CA, USA). The SGK-1 gene and its variants were investigated in CSC patient group and control group.RESULTS: We identified a new polymorphism M32 V in two person in the patient group [Minor allele frequency(MAF) =0.009] on the region of 1-60 amino acids. The rs1057293 was located in the encoder region of the SGK- 1 gene but not associated with CSC(P =0.68). An intrinsic rs1743966 is also not associated(P =0.28).CONCLUSION: The new polymorphism M32 V is located on the region of 1-60 amino acids which is necessary for localization to the mitochondria in CSC patient. This mutation is probably important for the energy metabolism and plays an important role in the cellular response to hyperosmotic stress and other stress stimuli. Both rs1057293 and rs1743966 are not associated with CSC.
文摘Background and Objective Marfan syndrome,a variable and heritable disorder of fibrous connective tissue,characterized by affecting skeletal,ocular and cardiovascular systems.With the research advancement of genetic mechanism,the diagnosis of Marfan syndrome,based on clinical manifestations and genetic evidence,is more accurate.The aim of this study is identification of genetic pathogenesis in a Chinese family.
基金Supported by the Health Special Research Projects of Military Commission (No.19BJZ39)the Key Research Plan of Hainan Province (No.ZDYF2020031)。
文摘AIM:To describe the clinical heterogeneity of patients with novel mutations in BEST1.METHODS:All the members in the two Chinese families underwent detailed clinical evaluations including best-corrected visual acuity,slit-lamp examination,applanation tonometry,and dilated fundus examination.Fundus autofluorescence,fundus fluorescein angiography,spectral-domain optical coherence tomography,electrooculography,and electroretinogram were also performed.Genomic DNA was extracted from venous blood for all the participants.The targeted next-generation sequencing of inherited retinal disease-associated genes was conducted to identify the causative mutation.RESULTS:A novel BEST1 missense mutation c.41T>C(p.Leu14Ser) was identified in Family 1.It was co-segregated with the phenotype of best vitelliform macular dystrophy(BVMD) and bioinformatics analysis confirmed it was harmful.Another novel BEST1 frameshift mutation c.345_(3)46insGGCAAGGACG(p.Glu119Glyfs*116) and a novel USH2A missense mutation c.12560G>A,p.Arg4187 His were identified in family 2 with retinitis pigmentosa(RP),which might interact and lead to the phenotype of RP.CONCLUSION:Two novel mutations in the BEST1 gene in two unrelated families with distinct phenotypes and BEST1 mutation accompanied with USH2A mutation would result in RP,which could be enormously helpful in understanding the pathogenesis of the inherited retinal disease caused by a BEST1 mutation.
基金Supported by Zhejiang Provincial Natural Science Foundation of China,No.LQ19H050003General Project Funds from the Health Department of Zhejiang Province,No.2020KY439.
文摘BACKGROUND Approximately 10%of adults and nearly all children who receive renal replacement therapy have inherited risk factors or are related to genetic factors.In the past,due to the limitations of detection technology and the nonspecific manifestations of uraemia,the etiological diagnosis is unclear.In addition to common monogenic diseases and complex disorders,advanced testing techniques have led to the recognition of more hereditary renal diseases.Here,we report a four-generation Chinese family in which four individuals had a novel SALL1 mutation and presented with uraemia or abnormal urine tests.CASE SUMMARY A 32-year-old man presented with end-stage renal disease with a 4-year history of dialysis.His father and paternal aunt both had a history of unexplained renal failure with haemodialysis,and his 10-year-old daughter presented with proteinuria.The patient had multiple congenital abnormalities,including bilateral overlapping toes,unilateral dysplastic external ears,and sensorineural hearing loss.His family members also presented with similar defects.Genetic testing revealed that the proband carried a novel heterozygous shift mutation in SALL1_exon 2(c.3437delG),and Sanger sequencing confirmed the same mutation in all affected family members.CONCLUSION We report a novel SALL1 exon 2(c.3437delG)mutation and clinical syndrome with kidney disease,bilateral overlapping toes,unilateral dysplastic external ears,and sensorineural hearing loss in a four-generation Chinese family.
文摘<strong>Background:</strong><span><span style="font-family:Verdana;"> Dental complications of Ehlers-Danlos syndrome (EDS) include periodontitis with gum fragility and inflammation, enamel hypoplasia with frequent caries, high palate with dental crowding, TMJ instability, sutur</span><span><span style="font-family:Verdana;">al dehiscence or scarring, and insensitivity to anesthetics. </span><b><span style="font-family:Verdana;">Objective:</span></b><span style="font-family:Verdana;"> Determine if EDS dental complications always define a specific type and genetic cause or if they can arise as a general consequence of altered inflammatory response in EDS. </span><b><span style="font-family:Verdana;">Method:</span></b><span style="font-family:Verdana;"> We compared findings of a 58-year-old female</span></span><span style="font-family:Verdana;"> with complement component 1R (C1R</span><span style="font-family:Verdana;">) </span><span style="font-family:Verdana;">gene mutation (c.1553A > T, p.Asp518Val) </span><span><span style="font-family:Verdana;">found by whole exome sequencing to 43 patients with C1R gene mutations ascertained because of periodontal disease and to 710 EDS patients conventially ascertained because of joint and skin laxity. </span><b><span style="font-family:Verdana;">Result:</span></b><span style="font-family:Verdana;"> Female patients ascertained as periodontal EDS showed the expected higher frequency of periodontitis (96% versus 14%) but had similar frequencies of hypermobility (81% versus 90%) and some skin findings (84% versus 92% with skin fragility) as the general group and our female patient who shared their </span><span style="font-family:Verdana;">C1R</span><span style="font-family:Verdana;"> gene change. Her oromandibular bone loss rather than gum dis</span></span><span><span style="font-family:Verdana;">ease may reflect the more carboxy-terminal position of her </span><span style="font-family:Verdana;"><span style="font-family:Verdana;">C</span></span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">1</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">R</span></span></span><span><span><span> </span></span></span><span style="font-family:Verdana;">gene mutatio</span><span><span style="font-family:Verdana;">n compared to those in the patients identified as periodontal EDS. </span><b><span style="font-family:Verdana;">Conclusion:</span></b> <span><span style="font-family:Verdana;">While mutation of the </span><span style="font-family:Verdana;">C1R </span><span style="font-family:Verdana;">gene may predict more frequent periodontal, skin, and vascular complications, focus on an articulo-autonomic dysplasia process that includes mast-cell activation and altered inflammatory response rather than extreme EDS types will help dentists and other subspecialists identify all EDS patients and anticipate their frequent oral manifestations.</span></span></span>
基金Supported by research grants from the 'Werner Otto Stiftung e.V.
文摘AIM: To verify and expand the known spectrum of serine protease inhibitor Kazal type 1 (SPINK1) gene mutations in chronic pancreatitis. METHODS: DNA extracted from 172 chronic pancreatitis patients was assayed for SPINK1 gene mutations by PCR and DNA sequencing. A control cohort of 90 unrelated healthy individuals was analysed by the same methods for presence of common populational polymorphisms, and frequency of five-loci haplotypes was calculated. Linkages of gene aberrations in single SPINK1 gene copies were analysed by long-distance PCR followed by allele-specifi c PCR and DNA sequencing. RESULTS: The most frequent SPINK1 gene mutation N34S was found at a frequency of 6%. Furthermore, we detected the heterozygous intervening sequence (IVS) 3 + 2 T > C mutated gene in 2 German patients and 1 Macedonian chronic pancreatitis patient. In all three SPINK1 gene copies an additional rare base substitution was found: 5’untranslated region (UTR)-215 G > A. Poly-morphism analysis revealed that all three affected genes carried the same fi ve-loci haplotype. DNA sequencing of another chronic pancreatitis-related gene PRSS1 (cationic trypsinogen) did not reveal any mutations in these 3 pa-tients.CONCLUSION: We found in 3 (2%) of 172 chronic pancreatitis patients an IVS3 + 2 T > C SPINK1 gene mutation and a base substitution 5’UTR-215 G > A inthe same gene copy. Most probably the 5’UTR-215 G >A represents a rare polymorphism and not a mutationas previously concluded. Haplotype analysis suggests acommon origin of the IVS3 + 2 T > C mutation in thesepatients.
基金National Science Foundation of China (NS-FC:No: 3880680 No: 39670643)
文摘Abstract Objective:To establish a reformative detection system which has sound ability of providing infor-mation on molecular mutagenesis spectrum and the specificity of detection system of repackaged λ phage.Methods:LacZ gene,as mutational target gene and reporter gene, was applied into the detection system.The λ gt11 DNA treated with ENU(1-ethyl-1-nitrosourea)and 9-AA(9-aminoacridine)was repackaged in vitro.The packaged λ phage was then grown in E.coli Y1090 on a selective plate containing X-gel and IPTG.The survival and mutation frequencies were determined by counting the clear-plaque and blue-plaque,and the molecular mutation mechanism was studied by extracting and sequencing the LacZ gene of mutants.Results:The survival of repackaged λ phages treated with 9-AA and ENU apparently decreased in consistent dose-dependence.The mutation frequency of clear-plaque mutants showed a linear dose-related increase.The predominant mutations induced by 9-AA were ±1 frameshift mutation, and 9-AA induced -1 frameshift was much more effective than induced +1 frameshift.9-AA also induced substitutions with transversions more common.ENU -induced mutations were chiefly occurred at G:C sites .Substitutions induced by ENU were mainly G:C→A:T,G:C→C:Gand A:T→T:A transversion.Conclusion;Mutation detection sys-tem of λgt 11 DNA containing LacZ gene is proven better than that of λDNA without LacZ gene.The combi-nation of survival, mutant frequency and sequence spectrum can not only increase the sensitivity and specifici-ty of the new method, but also provide a better understanding of the molecular mechanism of mutation for ul-timate extrapolation to risk assessment.
