FP763WHETHER WOMEN ASYMPTOMATIC OR SYMPTOMATIC CARRIERS OF DENT DISEASE?

Abstract

Introduction and Aims: Dent disease (DD) is an X-linked proximal tubulop-athy characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, and progression to end stage kidney disease (ESKD). The disease is caused by mutations in CLCN5 (OMIM 300008) or OCRL (OMIM 300555) genes and affects males, whereas female carriers are generally asymptomatic. The aim of the study was to characterize phenotype and genotype of patients' mothers with DD. Methods: We conducted clinical and genetic evaluation of 9 mothers with median age 35 (IQR: 32-39) years of 10 boys with DD from 8 unrelated families. Polymerase chain reaction-amplification and automated sequence analysis of CLCN5 and OCRL genes was carried out with genomic DNA obtained from white blood cells of all patients and their mothers. Results: Carrier status of DD 1 (n=7) and DD 2 types (n=2) was confirmed in all included patients' mothers. DNA analysis identified heterozygous mutations in CLCN5 gene: c.1909C>T (p.Arg637*) (n=2), c.731C>T (p.Ser244Leu) (n=2), c.211C>T (p.Arg707Ter) (n=1),c.842C>T (p.Ser281Leu) (n=1),c.206-2A>G (n=1),andin OCRL gene (n=2): c.316A>T (p.Lys106*) and c.1497C>T (p.Arg493Trp). Hypophosphatemia was found in 7 (77.8%) carrier females of DD. Decreased tubular reabsorption of phosphate (TRP) <85% had 6 (66.7%) women and ratio of the maximum rate of TRP to eGFR <0.90 mmol/L had 5 (55.6%) boys' mothers. Medullary nephrocalcinosis was revealed in 6 (66.7%) carrier females of DD. LMW proteinuria and hypercalciuria had 2 (22.2%) patients' mothers. CKD stage 2 had 6 (66.7%) women with median eGFR 81.5 (69.8; 86.8) ml/min/1.73 m2. Full phenotype of DD foud in 2 (22.2%) cousins-carrier females with DD 1 type. Nobody of the patients' mothers with DD was asymptomatic. Conclusions: We found that carrier females may develop symptoms of DD with a wide phenotypic variation. The most prevalent features of DD in patients' mothers were decreased TRP with hypophosphatemia, medullary nephrocalcinosis and progression to CKD 2 stage. We suppose that revealed clinical signs of DD in carrier females might be a consequence of autosome translocation or nonrandom X chromosome inactivation. These data suggest that clinicians should consider a diagnostic evaluation of boys' mothers with DD for early prevention of nephrocalcinosis and progression to ESKD.