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

BMC Medical Genetics

Gema Ariceta³  Amel Haj Khelil²  Luis Castaño⁴  Jemni Ben Chibani²  Samir Mrabet⁶  Féthi El Amri⁵  Mohamed Neji Gueddiche⁷  Wafa Ben Romdane⁶  Nadia Leban²  Monia Troudi⁵  Adnène Mlika⁵  Saber Hamami⁷  Slaheddine Chouchane⁷  Gustavo Perez de Nanclares¹  Donia Elhayek⁷ 

[1] Research Unit, Ciberer, Hospital Universitario Cruces, UPV-EHU, BioCruces, Bizkaia, Spain;Laboratory of Biochemistry and Molecular Biology, Faculty of Pharmacy, Monastir, Tunisia;Servicio de Nefrología Pediátrica y Hemodiálisis, Hospital Universitario Materno-Infantil Vall d’Hebron, Passeig de la Vall d’Hebron 119-129, Barcelona 08035, Spain;Department of Pediatrics, School of Medicine and Odontology, UPV/EHU, Bizkaia, Spain;Department of Pediatrics, Hospital Ibn El Jazar, Kairouan, Tunisia;Department of Pediatrics, Hospital Mohamed Ben Sassi, Gabes, Tunisia;Department of Pediatrics, Hospital Fattouma Bourguiba, Monastir, Tunisia

关键词: Tunisian population;    ATP6V0A4;    ATP6V1B1;    Distal renal tubular acidosis;   

Others  :  1122579
DOI  :  10.1186/1471-2350-14-119

 received in 2012-12-11, accepted in 2013-11-08,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Elhayek et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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