Document Detail

An atypical Dent's disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes.
MedLine Citation:
PMID:  23047739     Owner:  NLM     Status:  MEDLINE    
Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL gene, which is usually mutated in patients with Lowe syndrome, have been shown to lead to a Dent-like phenotype called Dent disease 2. However, about 20% of patients with Dent's disease carry no CLCN5/OCRL mutations. The disease's genetic heterogeneity is accompanied by interfamilial and intrafamilial phenotypic heterogeneity. We report on a case of Dent's disease with a very unusual phenotype (dysmorphic features, ocular abnormalities, growth delay, rickets, mild mental retardation) in which a digenic inheritance was discovered. Two different, novel disease-causing mutations were detected, both inherited from the patient's healthy mother, that is a truncating mutation in the CLCN5 gene (A249fs*20) and a donor splice-site alteration in the OCRL gene (c.388+3A>G). The mRNA analysis of the patient's leukocytes revealed an aberrantly spliced OCRL mRNA caused by in-frame exon 6 skipping, leading to a shorter protein, but keeping intact the central inositol 5-phosphatase domain and the C-terminal side of the ASH-RhoGAP domain. Only wild-type mRNA was observed in the mother's leukocytes due to a completely skewed X inactivation. Our results are the first to reveal the effect of an epistatic second modifier in Dent's disease too, which can modulate its expressivity. We surmise that the severe Dent disease 2 phenotype of our patient might be due to an addictive interaction of the mutations at two different genes.
Maria Addis; Cristiana Meloni; Enrica Tosetto; Monica Ceol; Rosalba Cristofaro; Maria Antonietta Melis; Paolo Vercelloni; Dorella Del Prete; Giuseppina Marra; Franca Anglani
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Publication Detail:
Type:  Case Reports; Journal Article     Date:  2012-10-10
Journal Detail:
Title:  European journal of human genetics : EJHG     Volume:  21     ISSN:  1476-5438     ISO Abbreviation:  Eur. J. Hum. Genet.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-16     Completed Date:  2013-10-21     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  9302235     Medline TA:  Eur J Hum Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  687-90     Citation Subset:  IM    
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MeSH Terms
Base Sequence
Chloride Channels / genetics*
DNA Mutational Analysis
Dent Disease / genetics*
Exons / genetics
Inheritance Patterns / genetics*
Introns / genetics
Molecular Sequence Data
Mutation / genetics*
Phosphoric Monoester Hydrolases / genetics*
Reg. No./Substance:
0/CLC-5 chloride channel; 0/Chloride Channels; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC protein, human

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