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Open Access Research article

Molecular diagnosis of distal renal tubular acidosis in Tunisian patients: proposed algorithm for Northern Africa populations for the ATP6V1B1, ATP6V0A4 and SCL4A1 genes

Donia Elhayek123, Gustavo Perez de Nanclares2, Slaheddine Chouchane3, Saber Hamami3, Adnène Mlika4, Monia Troudi4, Nadia Leban1, Wafa Ben Romdane5, Mohamed Neji Gueddiche3, Féthi El Amri4, Samir Mrabet5, Jemni Ben Chibani1, Luis Castaño26, Amel Haj Khelil1 and Gema Ariceta678*

Author Affiliations

1 Laboratory of Biochemistry and Molecular Biology, Faculty of Pharmacy, Monastir, Tunisia

2 Research Unit, Ciberer, Hospital Universitario Cruces, UPV-EHU, BioCruces, Bizkaia, Spain

3 Department of Pediatrics, Hospital Fattouma Bourguiba, Monastir, Tunisia

4 Department of Pediatrics, Hospital Ibn El Jazar, Kairouan, Tunisia

5 Department of Pediatrics, Hospital Mohamed Ben Sassi, Gabes, Tunisia

6 Department of Pediatrics, School of Medicine and Odontology, UPV/EHU, Bizkaia, Spain

7 Division of Pediatric Nephrology, Hospital Universitario Cruces, BioCruces, Bizkaia, Spain

8 Servicio de Nefrología Pediátrica y Hemodiálisis, Hospital Universitario Materno-Infantil Vall d’Hebron, Passeig de la Vall d’Hebron 119-129, Barcelona 08035, Spain

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BMC Medical Genetics 2013, 14:119  doi:10.1186/1471-2350-14-119

Published: 20 November 2013

Abstract

Background

Primary distal renal tubular acidosis (dRTA) caused by mutations in the genes that codify for the H + −ATPase pump subunits is a heterogeneous disease with a poor phenotype-genotype correlation. Up to now, large cohorts of dRTA Tunisian patients have not been analyzed, and molecular defects may differ from those described in other ethnicities. We aim to identify molecular defects present in the ATP6V1B1, ATP6V0A4 and SLC4A1 genes in a Tunisian cohort, according to the following algorithm: first, ATP6V1B1 gene analysis in dRTA patients with sensorineural hearing loss (SNHL) or unknown hearing status. Afterwards, ATP6V0A4 gene study in dRTA patients with normal hearing, and in those without any structural mutation in the ATP6V1B1 gene despite presenting SNHL. Finally, analysis of the SLC4A1 gene in those patients with a negative result for the previous studies.

Methods

25 children (19 boys) with dRTA from 20 families of Tunisian origin were studied. DNAs were extracted by the standard phenol/chloroform method. Molecular analysis was performed by PCR amplification and direct sequencing.

Results

In the index cases, ATP6V1B1 gene screening resulted in a mutation detection rate of 81.25%, which increased up to 95% after ATP6V0A4 gene analysis. Three ATP6V1B1 mutations were observed: one frameshift mutation (c.1155dupC; p.Ile386fs), in exon 12; a G to C single nucleotide substitution, on the acceptor splicing site (c.175-1G > C; p.?) in intron 2, and one novel missense mutation (c.1102G > A; p.Glu368Lys), in exon 11. We also report four mutations in the ATP6V0A4 gene: one single nucleotide deletion in exon 13 (c.1221delG; p.Met408Cysfs*10); the nonsense c.16C > T; p.Arg6*, in exon 3; and the missense changes c.1739 T > C; p.Met580Thr, in exon 17 and c.2035G > T; p.Asp679Tyr, in exon 19.

Conclusion

Molecular diagnosis of ATP6V1B1 and ATP6V0A4 genes was performed in a large Tunisian cohort with dRTA. We identified three different ATP6V1B1 and four different ATP6V0A4 mutations in 25 Tunisian children. One of them, c.1102G > A; p.Glu368Lys in the ATP6V1B1 gene, had not previously been described. Among deaf since childhood patients, 75% had the ATP6V1B1 gene c.1155dupC mutation in homozygosis. Based on the results, we propose a new diagnostic strategy to facilitate the genetic testing in North Africans with dRTA and SNHL.

Keywords:
Distal renal tubular acidosis; ATP6V1B1; ATP6V0A4; Tunisian population