Dent disease is a rare X-linked recessively inherited renal tubulopathy,caused by variants in the CLCN5(Dent disease type 1,DD1)and OCRL(Dent disease type 2,DD2)genes,and characterized by low molecular weight proteinu...Dent disease is a rare X-linked recessively inherited renal tubulopathy,caused by variants in the CLCN5(Dent disease type 1,DD1)and OCRL(Dent disease type 2,DD2)genes,and characterized by low molecular weight proteinuria,hypercalciuria,microscopic hematuria,or nephrocalcinosis.In the current study,we collected and analyzed clinical data and genetic testing results of 21 children diagnosed with Dent disease,who were hospitalized at the Department of Nephrology,Children's Hospital of Nanjing Medical University between January 2014 and August 2023,aiming to assist in the early diagnosis and treatment of these patients.Among the 21 patients,16(76.19%)had CLCN5 variants,and five(23.81%)had OCRL variants,and four of the variants were novel.All patients presented with low molecular weight proteinuria,14(66.67%)of whom had nephroticrange proteinuria.Eight patients underwent renal biopsies because of diagnostic uncertainty.We transfected the novel CLCN5 missense variant(p.G222R)and OCRL missense variant(p.I371T)plasmids into both HEK293 and HK-2 cells and found a significantly lower expression of the OCRL1 protein in the transfected cells than in the wild-type cells(P<0.05).Moreover,we observed an extremely skewed X-chromosome inactivation pattern in a female patient carrying the same novel CLCN5 variant,as assessed by the human androgen receptor gene assay.These findings provide insight into the clinical characteristics of Dent disease in Chinese patients and may shed light on its pathogenesis.展开更多
Background:Lowe syndrome,an X-linked,inheritable disease with clinical symptoms of congenital cataracts,incomplete Fanconi syndrome,and mental retardation,has an approximate incidence of 1 in 500000.Nearly 200 OCRL mu...Background:Lowe syndrome,an X-linked,inheritable disease with clinical symptoms of congenital cataracts,incomplete Fanconi syndrome,and mental retardation,has an approximate incidence of 1 in 500000.Nearly 200 OCRL mutations related to Lowe syndrome have been found worldwide,with only ten mutations among the Chinese population.Since more mutations may exist in Chinese patients,we sequenced and analyzed the OCRL genes of six children with Lowe syndrome in a medical center in China.Methods:Peripheral blood was collected from six children with Lowe syndrome and their relatives,and ten healthy adults.Genomic DNA was extracted from the blood and applied to amplify the twenty-four exons and flanking introns of the OCRL gene.The mutations were identified by sequencing.Results:Five mutations(c.1528C>T,c.2187insG,c.1366C>T,c.1499G>A,and c.2581G>A)of the OCRL gene were found in five families;c.2187insG and c.1366C>T were novel mutations.None of the five mutations were detected in 20 normal chromosomes.No mutation was found in the sixth family.Conclusion:Two novel mutations of the OCRL gene,c.2187insG and c.1366C>T,were found in Chinese patients with Lowe syndrome,which will provide new clues for the etiology of Lowe syndrome and could be beneficial to genetic diagnosis of the condition.展开更多
Background Dent disease is a rare tubulopathy characterized by manifestations of proximal tubular dysfunction,which occurs almost exclusively in males.It mainly presents symptoms in early childhood and may progress to...Background Dent disease is a rare tubulopathy characterized by manifestations of proximal tubular dysfunction,which occurs almost exclusively in males.It mainly presents symptoms in early childhood and may progress to end-stage renal failure between the 3rd and 5th decades of human life.According to its various genetic basis and to clinical signs and symp-toms,researchers define two forms of Dent disease(Dent diseases 1 and 2)and suggest that these forms are produced by mutations in the CLCN5 and OCRL genes,respectively.Dent diseases 1 and 2 account for 60% and 15% of all Dent disease cases,and their genetic cause is generally understood.However,the genetic cause of the remaining 25% of Dent disease cases remains unidentified.Data sources All relevant peer-reviewed original articles published thus far have been screened out from PubMed and have been referenced.Results Genetic testing has been used greatly to identify mutation types of CLCN5 and OCRL gene,and next-generation sequencing also has been used to identify an increasing number of unknown genotypes.Gene therapy may bring new hope to the treatment of Dent disease.The abuse of hormones and immunosuppressive agents for the treatment of Dent disease should be avoided to prevent unnecessary harm to children.Conclusions The current research progress in classification,genetic heterogeneity,diagnosis,and treatment of Dent disease reviewed in this paper enables doctors and researchers to better understand Dent disease and provides a basis for improved prevention and treatment.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.82200744)the Nanjing Science and Technology Development Funding(Grant No.YKK22159).
文摘Dent disease is a rare X-linked recessively inherited renal tubulopathy,caused by variants in the CLCN5(Dent disease type 1,DD1)and OCRL(Dent disease type 2,DD2)genes,and characterized by low molecular weight proteinuria,hypercalciuria,microscopic hematuria,or nephrocalcinosis.In the current study,we collected and analyzed clinical data and genetic testing results of 21 children diagnosed with Dent disease,who were hospitalized at the Department of Nephrology,Children's Hospital of Nanjing Medical University between January 2014 and August 2023,aiming to assist in the early diagnosis and treatment of these patients.Among the 21 patients,16(76.19%)had CLCN5 variants,and five(23.81%)had OCRL variants,and four of the variants were novel.All patients presented with low molecular weight proteinuria,14(66.67%)of whom had nephroticrange proteinuria.Eight patients underwent renal biopsies because of diagnostic uncertainty.We transfected the novel CLCN5 missense variant(p.G222R)and OCRL missense variant(p.I371T)plasmids into both HEK293 and HK-2 cells and found a significantly lower expression of the OCRL1 protein in the transfected cells than in the wild-type cells(P<0.05).Moreover,we observed an extremely skewed X-chromosome inactivation pattern in a female patient carrying the same novel CLCN5 variant,as assessed by the human androgen receptor gene assay.These findings provide insight into the clinical characteristics of Dent disease in Chinese patients and may shed light on its pathogenesis.
基金supported by grants from the Science and Technology Program of Guangzhou(201300000168)Guangdong Provincial Population and Family Planning Projects(2012263)
文摘Background:Lowe syndrome,an X-linked,inheritable disease with clinical symptoms of congenital cataracts,incomplete Fanconi syndrome,and mental retardation,has an approximate incidence of 1 in 500000.Nearly 200 OCRL mutations related to Lowe syndrome have been found worldwide,with only ten mutations among the Chinese population.Since more mutations may exist in Chinese patients,we sequenced and analyzed the OCRL genes of six children with Lowe syndrome in a medical center in China.Methods:Peripheral blood was collected from six children with Lowe syndrome and their relatives,and ten healthy adults.Genomic DNA was extracted from the blood and applied to amplify the twenty-four exons and flanking introns of the OCRL gene.The mutations were identified by sequencing.Results:Five mutations(c.1528C>T,c.2187insG,c.1366C>T,c.1499G>A,and c.2581G>A)of the OCRL gene were found in five families;c.2187insG and c.1366C>T were novel mutations.None of the five mutations were detected in 20 normal chromosomes.No mutation was found in the sixth family.Conclusion:Two novel mutations of the OCRL gene,c.2187insG and c.1366C>T,were found in Chinese patients with Lowe syndrome,which will provide new clues for the etiology of Lowe syndrome and could be beneficial to genetic diagnosis of the condition.
基金supported by National Natural Foundation of China(81470939&81770710)Natural Science Foundation of Zhejiang Province(LH14H050002,LY15H050001,LQ18H050001)Ai You Foundation.
文摘Background Dent disease is a rare tubulopathy characterized by manifestations of proximal tubular dysfunction,which occurs almost exclusively in males.It mainly presents symptoms in early childhood and may progress to end-stage renal failure between the 3rd and 5th decades of human life.According to its various genetic basis and to clinical signs and symp-toms,researchers define two forms of Dent disease(Dent diseases 1 and 2)and suggest that these forms are produced by mutations in the CLCN5 and OCRL genes,respectively.Dent diseases 1 and 2 account for 60% and 15% of all Dent disease cases,and their genetic cause is generally understood.However,the genetic cause of the remaining 25% of Dent disease cases remains unidentified.Data sources All relevant peer-reviewed original articles published thus far have been screened out from PubMed and have been referenced.Results Genetic testing has been used greatly to identify mutation types of CLCN5 and OCRL gene,and next-generation sequencing also has been used to identify an increasing number of unknown genotypes.Gene therapy may bring new hope to the treatment of Dent disease.The abuse of hormones and immunosuppressive agents for the treatment of Dent disease should be avoided to prevent unnecessary harm to children.Conclusions The current research progress in classification,genetic heterogeneity,diagnosis,and treatment of Dent disease reviewed in this paper enables doctors and researchers to better understand Dent disease and provides a basis for improved prevention and treatment.
