Distal renal tubular acidosis in a Libyan patient: Evidence for digenic inheritance
Introduction
Distal renal tubular acidosis (dRTA, MIM 602722) is characterized by impaired urine acidification due to the inability of the distal renal tubule to appropriately excrete H+ into the urine (Karet, 2009, Rodriguez Soriano, 2002), causing metabolic acidosis, often accompanied by hypokalemia, nephrocalcinosis, and/or nephrolithiasis (Elhayek et al., 2013, Karet et al., 1999, Shao et al., 2010).
The disease can be caused either by a defect in the H + -ATPase, which is responsible for acid (H+) secretion at the apical membrane of the epithelial α-intercalated cells or by an abnormality of the kidney anion exchanger 1 (kAE1) that functions in chloride (Cl−) and bicarbonate (HCO3−) anion exchange at the basolateral membrane. Both autosomal dominant (AD) and autosomal recessive (AR) inheritance patterns have been reported in primary dRTA.
Mutations in at least two genes ATP6V1B1 and ATP6V0A4, which encode the transmembrane a4 and catalytic b1 subunits of the apical H + -ATPase respectively, have been reported to cause autosomal recessive dRTA with sensorineural hearing loss (SNHL) or normal hearing (Karet et al., 1999, Ruf et al., 2003, Smith et al., 2000, Stover et al., 2002). Mutations in the SLC4A1 gene encoding the human AE1 have been associated with either AD or AR dRTA (Batlle and Haque, 2012, Sinha et al., 2013).
Additionally, the presence of sensorineural hearing loss (SNHL) in a patient who showed no mutation in ATP6V1B1 and ATP6V0A4 genes do not excluding a priori the possibility of a dRTA form related to a mutation in the SLC4A1 gene (Palazzo et al., 2017). The development of SNHL may also occur due to the consequences raised from non-genetic factors, such as ototoxic agents, neonatal distress and electrolyte disequilibrium.
Genetic analysis is required to further support the phenotype-genotype correlation in dRTA patients (Gao et al., 2014). Recent advances in genomics allowed mutation screening of enriched coding regions of the human genome in combination with next-generation sequencing to identify novel disease genes (Ng et al., 2010, Sanders, 2011, Walsh et al., 2010).
In this study, we initially screened ATP6V1B1 and ATP6V0A4 genes by direct sequencing in a young dRTA patient and then performed Whole Exome Sequencing (WES) to screen for mutations or large genomic rearrangements occurring in dRTA related or other genes. We reported two novel heterozygous mutations, one in each of the ATP6V1B1 and ATP6V0A4 genes in a Libyan dRTA patient with SNHL. Results highlight the possibility of digenic inheritance in dRTA, which in turn must be accounted in genetic counseling of individuals originating from Libya.
Section snippets
Patients
A two and a half years old patient from the North West of Libya, with its parents being first-cousins (third degree relatives), had severe clinical features in the first month after birth. The disease presented with hyperchloremia over 110 mmol/l, hypocalcaemia and normal plasma anion gap. This patient also showed digestive problems for several weeks, followed by fluid diarrhea and vomiting. Urinary tests showed a consistently higher urinary pH (8.3) and hypercalciuria. Radiologically, the
Results
Genetic analysis of one dRTA patient with additional SNHL, revealed two mutations in two different genes, ATP6V1B1 and ATP6V0A4, both previously associated with the trait, and the patient was heterozygous for both mutations.
Based on clinical data and since the patient presented with early bilateral deafness, molecular analysis commenced by the screening of ATP6V1B1. A novel variation (NM_001692.3: c.437A > G) was found in exon 5 in the heterozygous state. An aspartic acid residue (Asp, family
Discussion
This study is, to our knowledge, the first Libyan dRTA case that has been genetically studied. Reportedly, we identified two novel ATP6V1B1 and ATP6V0A4 in a single dRTA patient. This patient was heterozygous for a ATP6V1B1 missense mutation (p.Asp146Gly) and also heterozygous for p.Thr140Met in the ATP6V0A4 gene. It is postulated that the above variants, might be associated with the dRTA phenotype and it is remarkable in both cases the wild type acidic and polar residues respectively were
Conclusion
To our knowledge, this is the first study reporting the molecular investigation of a dRTA patient originating from Libya. Previous knowledge of a patient's ethnic background is essential in performing molecular diagnostics and must be taken into consideration for dRTA and other Mendelian diseases. The evidence shows that a novel heterozygous missense variant in ATP6V1B1, either paternal (unavailable) or spontaneous, and a previously reported heterozygous rare variant in ATP6V0A4 inherited from
Funding
This work was supported by the Tunisian Ministry of Public Health and the Ministry of Higher Education and Scientific Research (LR11IPT05), GENOMEDIKA FP7 project (Grant agreement No. 295097) and partly by a grant co-funded by the European Regional Development Fund and the Republic of Cyprus through the Research Promotion Foundation (Strategic Infrastructure Project NEW INFRASTRUCTURE/STRATEGIC/0308/24) to CD.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgements
We are grateful to the family members for their participation in this study.
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