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

Abstract

Aims: To investigate clinically and genetically all the distal renal tubular acidosis (dRTA) cases in Cyprus, to study one more family from Greece and to perform the first dRTA prenatal diagnosis. We also tried to find any association with sensorineural hearing loss (SNHL) onset and particular mutations. Methods: Nine dRTA families from Cyprus and one from Greece were analyzed for mutations in ATP6V1B1 gene by DNA resequencing and PCR-RFLPs. Clinical diagnosis was performed by standard criteria. Prenatal diagnosis was performed for one Cypriot family. Results: Results show that 7/9 dRTA cases in Cyprus are caused by 229+1G>T and R157C founder mutations in ATP6V1B1 gene. 229+1G>T mutation was estimated to be older than 400 years. No genotype- phenotype correlation was found with SNHL. A known (L81P) and a novel mutation (912delT) were found in the Greek family. Prenatal diagnosis was performed for one Cypriot family, after parents’ demand, showing that the embryo was a heterozygous carrier. Conclusion: Existence of only two ATP6V1B1 mutations in the Cypriot population is a diagnostic advantage. The age of onset of SNHL varies in our patients and probably is not related to ATP6V1B1 genotypes. Effective therapy for most of the syndrome symptoms is not satisfactory for some parents who choose prenatal diagnosis to ensure their child’s health.

Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss

“…Both patients' families originated from Kosovo and were not consanguineous and shared one mutation, the p.Leu81Pro on exon 3, suggesting that this mutation may be more common in this region. The same mutation was also previously found in a patient from Macedonia (4) and patients from Cyprus (11, 13). The second mutation in case I, p.Glu161Lys on exon 6, was described before as a SNP (4).…”

“…Mutations in ATP6V1B1 gene cause dRTA with or without SNHL (Table S3) (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The majority of these mutations are missense or nonsense mutations.…”

Molecular diagnosis of distal renal tubular acidosis in Tunisian patients: proposed algorithm for Northern Africa populations for the ATP6V1B1, ATP6V0A4 and SCL4A1genes

“…No phenotype-genotype correlation in dRTA with SNHL was detected in this cohort, as previously described [10]. On the other hand, this study confirms the association between ATP6V1B1 mutations and dRTA with early onset SNHL since childhood, and ATP6V0A4 mutations with dRTA but normal hearing (at least until young adulthood), as reported in the original disease genetic descriptions [7,8,18,25,26], but conflicts with some other reports [9,11], which described ATP6V0A4 gene mutations to be more frequent than ATP6V1B1 ones.…”

“…Indeed, Stover et al demonstrated that young adult patients with ATP6V0A4 mutations could develop mild SNHL in the long term [9]. Further, some dRTA patients without early SNHL were found to present mutations in the ATP6V1B1 gene as well [10,11]. …”

ATP6V1B1mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families

“…4 The H + -adenosine triphosphatase (ATPase) in the apical border of the intercalated cell of the distal nephron has a multisubunit structure that plays a role in pumping H + into the tubular lumen.5 To date, 26 ATP6V1B1 mutations have been determined as the cause of the disease. 4,6–13 These include missense, nonsense, deletion, insertion and splice site changes, all of which are predicted to disrupt the structure or abrogate the production, of the normal B1 subunit protein. This leads to loss of expression of the gene in the distal tubules as well as in cochlea and endolymphatic sac.…”