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Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and
N Akuta1, S E Lloyd, T Igarashi
1MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, England.
Insights
Japanese children with a progressive renal tubular disorder often have mutations in the CLCN5 gene. Identifying these CLCN5 mutations aids in early diagnosis and genetic evaluation for affected families.
Area of Science:
- Nephrology
- Human Genetics
- Molecular Biology
Background:
- A progressive renal tubular disorder, marked by low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis, affects over 60 Japanese children.
- This disorder exhibits familial predisposition, with prior studies linking it to mutations in the renal chloride channel gene, CLCN5.
Purpose of the Study:
- To investigate CLCN5 mutations in 10 unrelated Japanese families with the renal tubular disorder.
- To determine the prevalence of CLCN5 mutations in this patient cohort.
- To characterize the identified CLCN5 mutations and assess mutation screening methods.
Main Methods:
- Genetic analysis of the CLCN5 gene in patients from 10 unrelated Japanese families.
- Identification and characterization of mutations, including nonsense, frameshift, missense, deletion, and silent polymorphism.
- Mutation screening using single-stranded conformational polymorphism (SSCP) analysis.
Main Results:
- CLCN5 abnormalities were found in 7 out of 10 unrelated patients.
- Identified abnormalities included 5 mutations (2 nonsense, 1 frameshift, 2 missense), 1 deletion, and 1 silent polymorphism, with a clustering in CLCN5 exons 8 and 10.
- Over 80% of CLCN5 mutations were detectable by SSCP analysis.
Conclusions:
- Over 70% of Japanese patients with this renal tubulopathy possess CLCN5 mutations.
- CLCN5 mutations are a significant cause of this progressive renal tubular disorder in Japanese children.
- These findings facilitate the genetic and clinical evaluation of at-risk children.
Abstract:
The annual urinary screening of Japanese children above three years of age has identified a progressive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. The disorder has been observed in over 60 patients and has a familial predisposition. Mutations of a renal chloride channel gene, CLCN5, have been reported in four such families, and we have undertaken studies in additional patients from 10 unrelated, non-consanguineous Japanese families to further characterize such CLCN5 mutations and to ascertain their prevalence. CLCN5 abnormalities we identified in 7 of the 10 unrelated patients and consisted of 5 mutations (2 nonsense, 1 frameshift and 2 missense), 1 deletion and 1 silent polymorphism. A clustering of these mutations in CLCN5 exons 8 and 10 was observed. Over 80% of the CLCN5 mutations could be readily detected by single stranded conformational polymorphism (SSCP) analysis, thereby providing a useful mutation screening method. Our results, which indicate that over 70% of Japanese patients with this renal tubulopathy have CLCN5 mutations, will help in the genetic and clinical evaluation of children at risk from this disorder.