<strong>Introduction:</strong> Congenital hearing loss is the most common sensory deficit in the world and mutations in <em>GJB2</em> gene are the most common cause of deafness in many populati...<strong>Introduction:</strong> Congenital hearing loss is the most common sensory deficit in the world and mutations in <em>GJB2</em> gene are the most common cause of deafness in many populations. Frequency of <em>GJB2</em> mutations is estimated about 16% in Iran and varies among different provinces with a decreasing trend from north to south. The aim of this study was to investigate the frequency of <em>GJB2</em> mutations in Mazandaran province, north of Iran, among non-syndromic hearing loss patients. <strong>Methods:</strong> 262 patients from 204 families participated in this study. After genomic DNA extraction, <em>GJB2</em> gene analysis was carried out using DNA sequencing of both coding and non-coding regions by ABI 3130XL genetic analyzer. <strong>Results:</strong> 30.15% of all subjects showed mutations in GJB2 gene. Four mutations, including c.35delG (Gly12Valfs*), IVSI-1 + 1G > A, c.95G > A (Arg32His) and c.224 G > A (Arg75Gln) comprises 69.89% of all mutations in this study c.35delG and IVSI-1 were the most common mutations among patients respectively. Codon 75 mutation (c.224G > A. p: Arg75Gln) with autosomal dominant inheritance was seen in 7 cases from 3 families. 22 patients showed only one mutation in <em>GJB2</em> gene and in 126 (48.09%) individuals, parents had a consanguineous marriage. <strong>Discussion:</strong> Frequency of <em>GJB2</em> gene related hearing loss among patients was higher than average (16%) in this province. This study also showed a dominant inheritance pattern of <em>GJB2</em> gene in this area. Consanguineous marriage also showed highly frequent among parents. More investigation needs to clarify cause of hearing loss in those 22 patients with one mutation in <em>GJB2</em> gene, either two gene inheritance or another gene may be responsible for hearing loss.展开更多
Mutations in GJB2 gene are the most frequently found mutations in patients with nonsyndromic hearing impairment. However, the spectrum and prevalence of mutations in this gene vary among different ethnic groups. In Ch...Mutations in GJB2 gene are the most frequently found mutations in patients with nonsyndromic hearing impairment. However, the spectrum and prevalence of mutations in this gene vary among different ethnic groups. In China, 30,000 infants are born with congenital hearing impairment annually. In order to provide appropriate genetic testing and counseling to the families, we investigated the molecular etiology of nonsyndromic deafness in 103 unrelated school children attending Nantong School for the Deaf and Mute in Jiangsu Province, China. The coding exon of the GJB2 gene was PCR amplified and sequenced. Sixty two GJB2 mutant alleles were identified in 35.9% (37/103) of the patients. Twenty five patients carried two pathogenic mutations and 12 patients carried one mutant allele. The 235delC was the most common mutation accounting for 69.4% (43/62) of GJB2 mutant alleles. The GJB2 mutant alleles accounted for 30.1% (62/206) of all chromosomes responsible for nonsyndromic hearing impairment. Testing of the 3 most prevalent deleterious frame shift mutations in this cohort detected 100% of all GJB2 mutant alleles. These results demonstrate that an effective genetic testing of GJB2 gene for patients and families with nonsyndromic hearing impairment is possible.展开更多
AIM: To detect the pathogenetic mutations responsible for nonsyndromic autosomal recessive retinitis pigmentosa(RP) in 2 nonconsanguineous Chinese families. METHODS: The clinical data, including detailed medical histo...AIM: To detect the pathogenetic mutations responsible for nonsyndromic autosomal recessive retinitis pigmentosa(RP) in 2 nonconsanguineous Chinese families. METHODS: The clinical data, including detailed medical history, best corrected visual acuity(BCVA), slit-lamp biomicroscope examination, fundus photography, optical coherence tomography, static perimetry, and full field electroretinogram, were collected from the members of 2 nonconsanguineous Chinese families preliminarily diagnosed with RP. Genomic DNA was extracted from the probands and other available family members;wholeexome sequencing was conducted with the DNA samples provided by the probands, and all mutations detected by whole-exome sequencing were verified using Sanger sequencing in the probands and the other available family members. The verified novel mutations were further sequenced in 192 ethnicity matched healthy controls.RESULTS: The patients from the 2 families exhibited the typical symptoms of RP, including night blindness and progressive constriction of the visual field, and the fundus examinations showed attenuated retinal arterioles, peripheral bone spicule pigment deposits, and waxy optic discs. Whole-exome sequencing revealed a novel nonsense mutation in FAM161 A(c.943 A>T, p.Lys315*) and compound heterozygous mutations in RP1 L1(c.56 C>A, p.Pro19 His;c.5470 C>T, p.Gln1824*). The nonsense c.5470 C>T, p.Gln1824* mutation was novel. All mutations were verified by Sanger sequencing. The mutation p.Lys315* in FAM161A co-segregated with the phenotype, and all the nonsense mutations were absent from the ethnicity matched healthy controls and all available databases.CONCLUSION: We identify 2 novel mutations in genes responsible for autosomal recessive RP, and the mutation in FAM161A is reported for the first time in a Chinese population. Our result not only enriches the knowledge of the mutation frequency and spectrum in the genes responsible for nonsyndromic RP but also provides a new target for future gene therapy.展开更多
The mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and non-syndromic hearing loss. Of all the mutations, the homoplasmic A1555G and C1494T mutations ...The mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and non-syndromic hearing loss. Of all the mutations, the homoplasmic A1555G and C1494T mutations at a highly conserved decoding region in the 12S rRNA have been associated with aminoglycoside-induced and non-syndromic hearing loss in many families worldwide. The A1555G or C1494T mutation is expected to form novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the secondary structure of this RNA more closely resemble the corresponding region of bacterial 16S rRNA. Thus, the new U-A or G-C pair in 12S rRNA created by the C1494T or A1555G transition facilitates the binding of aminoglycosides, thereby accounting for the fact that the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying these mutations. Furthermore, the growth defect and impairment of mitochondrial translation were observed in cell lines carrying the A1555G or C1494T mutation in the presence of high concentration of aminoglycosides. In addition, nuclear modifier genes and mitochondrial haplotypes modulate the phenotypic manifestation of the A1555G and C1494T mutations. These observations provide the direct genetic and biochemical evidences that the A1555G or C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and nonsyndromic hearing loss. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside antibiotic therapy, and eventually to decrease the incidence of deafness.展开更多
Deafness is an etiologically heterogeneous trait with many known genetic, environmental causes or a combination thereof. The identification of more than 120 independent genes for deafness has provided profound new ins...Deafness is an etiologically heterogeneous trait with many known genetic, environmental causes or a combination thereof. The identification of more than 120 independent genes for deafness has provided profound new insights into the pathophysiology of hearing. However, recent findings indicate that a large proportion of both syndromic and nonsyndromic forms of deafness in Chinese population are caused by a small number of mutations. This review is focused on syndromic and nonsyndromic deafness as well as on the latest information linking inherited mitochondrial pathologies to a variety of etiologies of sensorineural deafness in Chinese population. Better understanding of the genetic causes of deafness in Chinese population is important for accurate genetics counseling and early diagnosis for timely intervention and treatment options.展开更多
文摘<strong>Introduction:</strong> Congenital hearing loss is the most common sensory deficit in the world and mutations in <em>GJB2</em> gene are the most common cause of deafness in many populations. Frequency of <em>GJB2</em> mutations is estimated about 16% in Iran and varies among different provinces with a decreasing trend from north to south. The aim of this study was to investigate the frequency of <em>GJB2</em> mutations in Mazandaran province, north of Iran, among non-syndromic hearing loss patients. <strong>Methods:</strong> 262 patients from 204 families participated in this study. After genomic DNA extraction, <em>GJB2</em> gene analysis was carried out using DNA sequencing of both coding and non-coding regions by ABI 3130XL genetic analyzer. <strong>Results:</strong> 30.15% of all subjects showed mutations in GJB2 gene. Four mutations, including c.35delG (Gly12Valfs*), IVSI-1 + 1G > A, c.95G > A (Arg32His) and c.224 G > A (Arg75Gln) comprises 69.89% of all mutations in this study c.35delG and IVSI-1 were the most common mutations among patients respectively. Codon 75 mutation (c.224G > A. p: Arg75Gln) with autosomal dominant inheritance was seen in 7 cases from 3 families. 22 patients showed only one mutation in <em>GJB2</em> gene and in 126 (48.09%) individuals, parents had a consanguineous marriage. <strong>Discussion:</strong> Frequency of <em>GJB2</em> gene related hearing loss among patients was higher than average (16%) in this province. This study also showed a dominant inheritance pattern of <em>GJB2</em> gene in this area. Consanguineous marriage also showed highly frequent among parents. More investigation needs to clarify cause of hearing loss in those 22 patients with one mutation in <em>GJB2</em> gene, either two gene inheritance or another gene may be responsible for hearing loss.
基金This work was supported by the Chinese National Nature Science Foundation research Grant 30572015Beijing Nature Science Foundation research Grant 7062062.
文摘Mutations in GJB2 gene are the most frequently found mutations in patients with nonsyndromic hearing impairment. However, the spectrum and prevalence of mutations in this gene vary among different ethnic groups. In China, 30,000 infants are born with congenital hearing impairment annually. In order to provide appropriate genetic testing and counseling to the families, we investigated the molecular etiology of nonsyndromic deafness in 103 unrelated school children attending Nantong School for the Deaf and Mute in Jiangsu Province, China. The coding exon of the GJB2 gene was PCR amplified and sequenced. Sixty two GJB2 mutant alleles were identified in 35.9% (37/103) of the patients. Twenty five patients carried two pathogenic mutations and 12 patients carried one mutant allele. The 235delC was the most common mutation accounting for 69.4% (43/62) of GJB2 mutant alleles. The GJB2 mutant alleles accounted for 30.1% (62/206) of all chromosomes responsible for nonsyndromic hearing impairment. Testing of the 3 most prevalent deleterious frame shift mutations in this cohort detected 100% of all GJB2 mutant alleles. These results demonstrate that an effective genetic testing of GJB2 gene for patients and families with nonsyndromic hearing impairment is possible.
基金Supported by the National Natural Science Foundation of China(No.81360154)
文摘AIM: To detect the pathogenetic mutations responsible for nonsyndromic autosomal recessive retinitis pigmentosa(RP) in 2 nonconsanguineous Chinese families. METHODS: The clinical data, including detailed medical history, best corrected visual acuity(BCVA), slit-lamp biomicroscope examination, fundus photography, optical coherence tomography, static perimetry, and full field electroretinogram, were collected from the members of 2 nonconsanguineous Chinese families preliminarily diagnosed with RP. Genomic DNA was extracted from the probands and other available family members;wholeexome sequencing was conducted with the DNA samples provided by the probands, and all mutations detected by whole-exome sequencing were verified using Sanger sequencing in the probands and the other available family members. The verified novel mutations were further sequenced in 192 ethnicity matched healthy controls.RESULTS: The patients from the 2 families exhibited the typical symptoms of RP, including night blindness and progressive constriction of the visual field, and the fundus examinations showed attenuated retinal arterioles, peripheral bone spicule pigment deposits, and waxy optic discs. Whole-exome sequencing revealed a novel nonsense mutation in FAM161 A(c.943 A>T, p.Lys315*) and compound heterozygous mutations in RP1 L1(c.56 C>A, p.Pro19 His;c.5470 C>T, p.Gln1824*). The nonsense c.5470 C>T, p.Gln1824* mutation was novel. All mutations were verified by Sanger sequencing. The mutation p.Lys315* in FAM161A co-segregated with the phenotype, and all the nonsense mutations were absent from the ethnicity matched healthy controls and all available databases.CONCLUSION: We identify 2 novel mutations in genes responsible for autosomal recessive RP, and the mutation in FAM161A is reported for the first time in a Chinese population. Our result not only enriches the knowledge of the mutation frequency and spectrum in the genes responsible for nonsyndromic RP but also provides a new target for future gene therapy.
文摘The mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and non-syndromic hearing loss. Of all the mutations, the homoplasmic A1555G and C1494T mutations at a highly conserved decoding region in the 12S rRNA have been associated with aminoglycoside-induced and non-syndromic hearing loss in many families worldwide. The A1555G or C1494T mutation is expected to form novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the secondary structure of this RNA more closely resemble the corresponding region of bacterial 16S rRNA. Thus, the new U-A or G-C pair in 12S rRNA created by the C1494T or A1555G transition facilitates the binding of aminoglycosides, thereby accounting for the fact that the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying these mutations. Furthermore, the growth defect and impairment of mitochondrial translation were observed in cell lines carrying the A1555G or C1494T mutation in the presence of high concentration of aminoglycosides. In addition, nuclear modifier genes and mitochondrial haplotypes modulate the phenotypic manifestation of the A1555G and C1494T mutations. These observations provide the direct genetic and biochemical evidences that the A1555G or C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and nonsyndromic hearing loss. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside antibiotic therapy, and eventually to decrease the incidence of deafness.
基金This study is supported by grants from NIH DC R01 05575(USA)and NSFC 30528025(China)to LIU Xuezhong.
文摘Deafness is an etiologically heterogeneous trait with many known genetic, environmental causes or a combination thereof. The identification of more than 120 independent genes for deafness has provided profound new insights into the pathophysiology of hearing. However, recent findings indicate that a large proportion of both syndromic and nonsyndromic forms of deafness in Chinese population are caused by a small number of mutations. This review is focused on syndromic and nonsyndromic deafness as well as on the latest information linking inherited mitochondrial pathologies to a variety of etiologies of sensorineural deafness in Chinese population. Better understanding of the genetic causes of deafness in Chinese population is important for accurate genetics counseling and early diagnosis for timely intervention and treatment options.
