BACKGROUND：7,12-dimethylbenzanthracene（DMBA）-induced pancreatic intraepithelial neoplasia（PanIN）and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic ...BACKGROUND：7,12-dimethylbenzanthracene（DMBA）-induced pancreatic intraepithelial neoplasia（PanIN）and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic cancer.However,this model has not been characterized genetically,and in particular,the major genetic alterations in the p16 gene are unknown.METHODS： Lesions of PanlN and pancreatic cancer were induced with DMBA implantation in 40 rats, and control pancreatic tissue was obtained from 10 age-matched rats without exposure to DMBA. Pancreatic tissue was harvested three months after DMBA implantation and DNA was extracted. Homozy- gous deletions and point mutations of the pl6 （exons 1 and 2） gene were detected by PCR amplification and direct sequencing. RESULTS： DMBA implantation in the 40 rats induced 26 Pan- INs and 9 carcinomas. The overall frequency of p 16 alterations in the pancreatic tissue of these rats was 42.86% （15/35）, and the changes were point mutations, not homozygous deletions. p16 mutations were present in 30.77% （8/26） of the rats with PanIN and 77.78% （7/9） of the rats with carcinoma （P〈0.05）. The increasing incidence of p16 alterations was detected in 20.00% （1/5） of PanIN-1, 28.57% （2/7） of PanIN-2 and 35.71% （5/14） of PanIN-3 lesions. CONCLUSION： Our findings indicated that p16 alteration is a common event in the carcinogenesis of this model and that the mutation pattern is analogous to that of human lesions.展开更多
BACKGROUND Dubin-Johnson syndrome(DJS)is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene.It is characterized by chronic or intermittent conjugated hyperbilirubinemia,with chronic idiop...BACKGROUND Dubin-Johnson syndrome(DJS)is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene.It is characterized by chronic or intermittent conjugated hyperbilirubinemia,with chronic idiopathic jaundice as the main clinical manifestation.Genetic alterations of the ABCC2 gene are commonly used for diagnosing DJS;however,the causative ABCC2 point mutation in Chinese patients remains unknown.Research on ABCC2 mutations in Chinese DJS patients is extremely rare,and the diagnosis of DJS remains limited.The routine analysis of ABCC2 mutations is helpful for the diagnosis of DJS.Here,we report the clinical characteristics and ABCC2 genotype of an adult female DJS patient.This article is to expound the discovery of more potentially pathogenic ABCC2 variants will that contribute to DJS identification.CASE SUMMARY This study investigated a woman referred for DJS and involved clinical and genetic analyses.ABCC2 mutations were identified by next-generation sequencing(NGS).The patient showed intermittent jaundice and conjugated hyperbilirubinemia.Histopathological examinations were consistent with the typical phenotype of DJS.Genetic diagnostic analysis revealed an ABCC2 genotype exhibiting a pathogenic variant,namely c.2443C>T(p.Arg815*),which has not been reported previously in the domestic or foreign literature.CONCLUSION Pathogenic ABCC2 mutations play an important role in the diagnosis of DJS,especially in patients with atypical presentations.Currently,NGS is used in the routine analysis of DJS cases and such tests of further cases will better illuminate the relationship between various genotypes and phenotypes of DJS.展开更多
Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 N...Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 NDD-related genes in 3,195 Chinese probands with neurodevelopmental phenotypes and identify 2,522 putative functional mutations consisting of 137 de novo mutations(DNMs)in 86 genes and 2,385 rare inherited mutations(RIMs)with 22 X-linked hemizygotes in 13 genes,2 homozygous mutations in 2 genes and 23 compound heterozygous mutations in 10 genes.Furthermore,the DNMs of16,807 probands with NDDs are retrieved from public datasets and combine in an integrated analysis with the mutation data of our Chinese NDD probands by taking 3,582 in-house controls of Chinese origin as background.We prioritize 26 novel candidate genes.Notably,six of these genes d ITSN1,UBR3,CADM1,RYR3,FLNA,and PLXNA3 d preferably contribute to autism spectrum disorders(ASDs),as demonstrated by high co-expression and/or interaction with ASD genes confirmed via rescue experiments in a mouse model.Importantly,these genes are differentially expressed in the ASD cortex in a significant manner and involved in ASD-associated networks.Together,our study expands the genetic spectrum of Chinese NDDs,further facilitating both basic and translational research.展开更多
基金supported by a grant from the National Natural Science Foundation of China(30972903)
文摘BACKGROUND：7,12-dimethylbenzanthracene（DMBA）-induced pancreatic intraepithelial neoplasia（PanIN）and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic cancer.However,this model has not been characterized genetically,and in particular,the major genetic alterations in the p16 gene are unknown.METHODS： Lesions of PanlN and pancreatic cancer were induced with DMBA implantation in 40 rats, and control pancreatic tissue was obtained from 10 age-matched rats without exposure to DMBA. Pancreatic tissue was harvested three months after DMBA implantation and DNA was extracted. Homozy- gous deletions and point mutations of the pl6 （exons 1 and 2） gene were detected by PCR amplification and direct sequencing. RESULTS： DMBA implantation in the 40 rats induced 26 Pan- INs and 9 carcinomas. The overall frequency of p 16 alterations in the pancreatic tissue of these rats was 42.86% （15/35）, and the changes were point mutations, not homozygous deletions. p16 mutations were present in 30.77% （8/26） of the rats with PanIN and 77.78% （7/9） of the rats with carcinoma （P〈0.05）. The increasing incidence of p16 alterations was detected in 20.00% （1/5） of PanIN-1, 28.57% （2/7） of PanIN-2 and 35.71% （5/14） of PanIN-3 lesions. CONCLUSION： Our findings indicated that p16 alteration is a common event in the carcinogenesis of this model and that the mutation pattern is analogous to that of human lesions.
基金Supported by The Talents of Qiankehe platform of China,No.[2018]5779-40the Zhuke Contract,No.[2018]1-92and the Qiankehe Support,No.[2017]2874.
文摘BACKGROUND Dubin-Johnson syndrome(DJS)is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene.It is characterized by chronic or intermittent conjugated hyperbilirubinemia,with chronic idiopathic jaundice as the main clinical manifestation.Genetic alterations of the ABCC2 gene are commonly used for diagnosing DJS;however,the causative ABCC2 point mutation in Chinese patients remains unknown.Research on ABCC2 mutations in Chinese DJS patients is extremely rare,and the diagnosis of DJS remains limited.The routine analysis of ABCC2 mutations is helpful for the diagnosis of DJS.Here,we report the clinical characteristics and ABCC2 genotype of an adult female DJS patient.This article is to expound the discovery of more potentially pathogenic ABCC2 variants will that contribute to DJS identification.CASE SUMMARY This study investigated a woman referred for DJS and involved clinical and genetic analyses.ABCC2 mutations were identified by next-generation sequencing(NGS).The patient showed intermittent jaundice and conjugated hyperbilirubinemia.Histopathological examinations were consistent with the typical phenotype of DJS.Genetic diagnostic analysis revealed an ABCC2 genotype exhibiting a pathogenic variant,namely c.2443C>T(p.Arg815*),which has not been reported previously in the domestic or foreign literature.CONCLUSION Pathogenic ABCC2 mutations play an important role in the diagnosis of DJS,especially in patients with atypical presentations.Currently,NGS is used in the routine analysis of DJS cases and such tests of further cases will better illuminate the relationship between various genotypes and phenotypes of DJS.
基金supported by the Guangdong Key Project in“Development of new tools for diagnosis and treatment of Autism”(2018B030335001 to Z.Sun)and“Early diagnosis and treatment of autism spectrum disorders”(202007030002 to Z.Sun)the National Natural Science Foundation of China(32070590 to Y.Wang)+5 种基金the National Natural Science Foundation of China(81730036 and81525007 to K.Xia)Science and Technology Major Project of Hunan Provincial Science and Technology Department(2018SK1030 to K.Xia)the National Natural Science Foundation of China(81801133 to J.Li)the Young Elite Scientist Sponsorship Program by CAST(2018QNRC001 to J.Li)the Innovation-Driven Project of Central South University(20180033040004 to J.Li)Natural Science Foundation of Hunan Province for outstanding Young Scholars(2020JJ3059 to J.Li)。
文摘Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 NDD-related genes in 3,195 Chinese probands with neurodevelopmental phenotypes and identify 2,522 putative functional mutations consisting of 137 de novo mutations(DNMs)in 86 genes and 2,385 rare inherited mutations(RIMs)with 22 X-linked hemizygotes in 13 genes,2 homozygous mutations in 2 genes and 23 compound heterozygous mutations in 10 genes.Furthermore,the DNMs of16,807 probands with NDDs are retrieved from public datasets and combine in an integrated analysis with the mutation data of our Chinese NDD probands by taking 3,582 in-house controls of Chinese origin as background.We prioritize 26 novel candidate genes.Notably,six of these genes d ITSN1,UBR3,CADM1,RYR3,FLNA,and PLXNA3 d preferably contribute to autism spectrum disorders(ASDs),as demonstrated by high co-expression and/or interaction with ASD genes confirmed via rescue experiments in a mouse model.Importantly,these genes are differentially expressed in the ASD cortex in a significant manner and involved in ASD-associated networks.Together,our study expands the genetic spectrum of Chinese NDDs,further facilitating both basic and translational research.
