AIM: To investigate the phenotype and genotype of a family with X-linked recessive Lowe syndrome. METHODS: All the members in the Chinese pedigree underwent comprehensive ophthalmologic and systemic examinations. Geno...AIM: To investigate the phenotype and genotype of a family with X-linked recessive Lowe syndrome. METHODS: All the members in the Chinese pedigree underwent comprehensive ophthalmologic and systemic examinations. Genomic DNA was isolated from peripheral blood of the pedigree members and 100 unrelated healthy Chinese subjects. Direct sequencing was performed to screen the exons and intron boundaries of OCRL.RESULTS: The ophthalmological and systemic exami nations suggested that the affected individual had Lowe syndrome. The phenotype in the pedigree is severe and consistent among all the affected individuals except for an individual who additionally suffered from congenital heart disease and laryngeal cartilage dysplasia. Directio nal San ger sequenci ng identified a complex mutation c.(2368_2368delG;c.2370A>C) in the Rho-GTPase activating protein domain. This complex mutation causes termination of protein synthesis at amino acid 824 and result in a new peptide with 823 amino acids (p.Ala790ProfsX34). This mutation was not detected in 100 unrelated healthy Chinese subjects.CONCLUSION: Our findings expand the phenotypic and genotypic spectrum of Lowe syndrome.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
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
基金Supported by the National Natural Science Foundation of China(No.81700812)the Ph.D.Start-up Fund of Natural Science Foundation of Guangdong Province(No.2017A030310214)the Guangdong Provincial Foundation for Medical Scientific Research(No.A2017016)
文摘AIM: To investigate the phenotype and genotype of a family with X-linked recessive Lowe syndrome. METHODS: All the members in the Chinese pedigree underwent comprehensive ophthalmologic and systemic examinations. Genomic DNA was isolated from peripheral blood of the pedigree members and 100 unrelated healthy Chinese subjects. Direct sequencing was performed to screen the exons and intron boundaries of OCRL.RESULTS: The ophthalmological and systemic exami nations suggested that the affected individual had Lowe syndrome. The phenotype in the pedigree is severe and consistent among all the affected individuals except for an individual who additionally suffered from congenital heart disease and laryngeal cartilage dysplasia. Directio nal San ger sequenci ng identified a complex mutation c.(2368_2368delG;c.2370A>C) in the Rho-GTPase activating protein domain. This complex mutation causes termination of protein synthesis at amino acid 824 and result in a new peptide with 823 amino acids (p.Ala790ProfsX34). This mutation was not detected in 100 unrelated healthy Chinese subjects.CONCLUSION: Our findings expand the phenotypic and genotypic spectrum of Lowe syndrome.
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 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.
