الفهرس 
AcknowledgementOnly 14 pages are availabe for public view
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Abstract
Renal tubular acidosis (RTA) is characterized by hyperchloremic metabolic acidosis with a normal anion gap. Four clinical types are now recognized but the number of possible causes is large. The study comprised 17 Egyptian families having index cases with documented inherited forms of RTA. The total number of screened probands was 22. The total number of screened relatives was 79. The total number of probands with documented mutations was 9 probands. The total number of carriers was 31. The patients were recruited consecutively in the period from November 2009 to February 2012. Our families were categorized as follow: three families of Fanconi-Bickel syndrome (FBS), two families of cystinosis and 12 families of distal RTA. All patients were subjected to a thorough history, pedigrees construction, full clinical examination, laboratory investigations and radiological investigations (plain x-rays, abdominal ultrasound and ECHO). Liver biopsy was done for those with hepatomegaly. Molecular workup was done in the form of DNA extraction, agarose gel electrophoresis, PCR of the extracted DNA and DNA sequencing for the specific gene according to each disease. We found five novel mutations out of the detected seven mutations in Egyptian population related to inherited RTA (two for FBS, one for cystinosis and two for distal RTA). As regards FBS: we re-enumerated (c.1250C>T) missense mutation to exon 10 instead of exon 9 of GLUT2 gene. The novel frameshift mutation (c.253_254delGA or p.Glu85fs) in exon 3 of GLUT2 gene was associated with more severe clinical manifestations. As regards cystinosis, the co-existence of two mutations, (c.18_21del) in exon 3 of CTNS gene together with splicing mutation (c.971–12G>A) causing a (G>A) substitution in between intron 11 and exon 12 of CTNS gene, modifies the phenotype of the disease. There was a high frequency of the known (c.18_21del) in exon 3 of CTNS gene. While, the splicing mutation (c.971–12G>A) between intron 11 and exon 12 was rare. As regards distal RTA, the deletion (c.1332_1335delTCT) in exon 14 of the ATP6V0A4 gene (Phe445del) was linked to a severe form of dRTA. The substitution (c.639+1G>A), causing a loss of a donor splice site between exon 8 and intron 8 of ATP6V0A4 gene, was associated with other renal tubular defects other than impaired acid secretion. No mutations had been detected in the studied loci in ten families of dRTA providing further evidence for additional genetic heterogeneity for this disease. We recommended extensive global studies for Egyptian families with RTA using sequencing analysis for all family members for the target gene clusters. We also recommend visiting Gene Atlas and HGMD before enumeration of mutations to certain exon of the studied gene. Also clinical follow up of cases of RTA is mandatory aiming for adding new parameters that are expected to affect the disease outcome.