Molecular investigation and long‐term clinical progress in Greek Cypriot families with recessive distal renal tubular acidosis and sensorineural deafness due to mutations in the ATP6V1B1 gene

Abstract

The spectrum of distal renal tubular acidosis (dRTA) includes a genetically heterogeneous group of inherited conditions of both autosomal-dominant and recessive mode of inheritance. The basic defect is linked to the renal part of acid-base homeostasis, which is partly achieved by the regulated luminal secretion of H+ at the apical surface of the alpha-intercalated cells of renal collecting ducts. This is coupled to bicarbonate reabsorption with chloride counter transport across the basolateral membranes. Here, we describe the molecular findings of the first two Greek Cypriot families with recessive dRTA and the long-term clinical findings in four of five affected members. DNA linkage analysis with four polymorphic markers flanking the ATP6V1B1 gene on chromosome 2 gave evidence for positive linkage; direct DNA analysis by automated DNA sequencing revealed that patients in one family were homozygous for mutation 229+1G>T (IVS7+1G>T) and that patients in the second family were compound heterozygous for 229+1G>T and R157C. The mutations were found on four different haplotypes. Both the mutations were previously reported in patients of Turkish origin. Three known polymorphic variants were also identified. The five patients demonstrated the whole clinical spectrum of the disease including death in infancy, failure to thrive, rickets, nephrocalcinosis, nephrolithiasis, and episodes of hypokalemic paralysis. Some of the family members are now in their mid 30s and late 20s, and nephrolithiasis with recurrent renal colics is their main problem. Renal function has remained normal. In conclusion, early diagnosis in infancy and prompt treatment with alkali and potassium supplements is of great benefit to the patient with dRTA and ensures normal growth. The identification of responsible mutations facilitates antenatal or postnatal diagnosis in concerned families and improves the prognosis.

Founder Mutations in the <i>ATP6V1B1 </i>GeneExplain Most Cypriot Cases of Distal Renal Tubular Acidosis: First Prenatal Diagnosis

“…Families CY8051 and CY8052 have previously been described in detail [6]. In two of the new families no mutations were identified.…”

“…DNA linkage studies and DNA sequence analysis of the ATP6V1B1 gene in two Greek- Cypriot families that presented with autosomal recessive inheritance of the disease revealed 229+1G>T mutation in homozygosity in patients of the first family, CY8051, and in compound heterozygosity with R157C mutation in the second family, CY8052 [6]. …”

Comparative Characteristics of Rickets-Like Diseases

“…В 1936 г. швейцарский педиатр G. Fanconi предложил гипо-тезу о тубулярной сущности заболевания. Для дан-ного синдрома характерными являются три ос-новных лабораторных признака: глюкозурия, генерализованная гипераминоацидурия и гипер-фосфатурия, развитие которых обусловлено ком-бинированной тубулопатией [26,27]. Синдром де Тони-Дебре-Фанкони является наиболее тяжелой формой патологии с рахитоподобными изменения-ми скелета из всех наследственных тубулопатий смешанного типа.…”

“…Появляется глюкозу-рия, генерализованная гипераминоацидурия (не со-провождается повышением содержания аминокислот в крови), полиурия, увеличение pH мочи, снижение уровня натрия и калия, в крови повышается содержа-ние молочной и пировиноградной кислот. Повышен-ная экскреция натрия и калия сопровождается разви-тием гипоизостенурии [26,27,30]. Лечение.…”

“…Лечение. Комплексное лечение проводится по не-скольким направлениям: коррекция электролитных нарушений, устранение сдвигов в кислотно-щелоч-ном равновесии, ликвидация дефицита калия и би-карбонатов, применение симптоматических средств [26,28]. При применении витамина D и его метабо-литов необходим постоянный контроль за почечной экскрецией кальция [4,29,30].…”