Hereditary nonsyndromic hearing impairment (HI) is extremely heterogeneous. Mutations of the transmembrane channel-like gene 1 (TMC1) have been shown to cause autosomal dominant and recessive forms of nonsyndromic HI linked to the loci DFNA36 and DFNB7/B11, respectively. TMC1 is 1 member of a family of 8 genes encoding transmembrane proteins. In the mouse, MmTmc1 and MmTmc2 are both members of Tmc subfamily A and are highly and almost exclusively expressed in the cochlea. The restricted expression of Tmc2 in the cochlea and its close phylogenetic relationship to Tmc1 makes it a candidate gene for nonsyndromic HI. We analyzed 3 microsatellite markers linked to the TMC1 and TMC2 genes in 85 Tunisian families with autosomal recessive nonsyndromic HI and without mutations in the protein-coding region of the GJB2 gene. Autozygosity by descent analysis of 2 markers bordering the TMC2 gene allowed us to rule out its association with deafness within these families. However, 5 families were found to segregate deafness with 3 different alleles of marker D9S1837, located within the first intron of the TMC1 gene. By DNA sequencing of coding exons of TMC1 in affected individuals, we identified 3 homozygous mutations, c.100C→T (p.R34X), c.1165C→T (p.R389X) and the novel mutation c.1764G→A (p.W588X). We additionally tested 60 unrelated deaf Tunisian individuals for the c.100C→T mutation. We detected this mutation in a homozygous state in 2 cases. This study confirms that mutations in the TMC1 gene may be a common cause for autosomal recessive nonsyndromic HI.

SummaryHereditary hearing impairment is the most genetically heterogeneous trait known in humans. So far, 50 published autosomal recessive non-syndromic hearing impairment (ARNSHI) loci have been mapped, and 23 ARNSHI genes have been identified. Here, we report the mapping of a novel ARNSHI locus, DFNB63, to chromosome 11q13.3-q13.4 in a large consanguineous Tunisian family. A maximum LOD score of 5.33 was obtained with microsatellite markers D11S916 and D11S4207. Haplotype analysis defined a 5.55 Mb critical region between microsatellite markers D11S4136 and D11S4081. DFNB63 represents the sixth ARNSHI locus mapped to chromosome 11. We positionally excluded MYO7A from being the DFNB63-causative gene. In addition, the screening of two candidate genes, SHANK2 and KCNE3, failed to reveal any disease-causing mutations.

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Background/Aims: Allgrove syndrome is a rare autosomal recessive disorder characterized by alacrima, achalasia, and adrenal insufficiency. It is caused by mutations of the AAAS gene located on chromosome 12q13 encoding the WD-repeat protein ALADIN. The c.1331+1G>A mutation is one of the most common mutations described in the literature and was identified in Tunisian and Algerian populations. Herein, we describe the clinical and genetic profile of two families from Libya in North Africa associated with Allgrove syndrome. Methods: Two unrelated families clinically diagnosed with Allgrove syndrome were evaluated for sequence variations in the AAAS gene. Blood samples were collected, and isolated DNA derived from the subjects was amplified. The entire sequence of the AAAS gene was analyzed by PCR-RFLP and direct sequencing. Results: Molecular analysis revealed the major homozygous mutation (c.1331+1G>A) in all patients. The presence of a major mutation in Tunisia, Algeria and, as discovered in this report, in Libya in patients with Allgrove syndrome suggests the existence of an ancestral mutation and a founder effect in North Africa. Conclusions: The findings allow for a fast genetic counseling in North African families with Allgrove syndrome. To the best of our knowledge, this is the first report of Allgrove syndrome in Libya.

Patients with classical Rett show an apparently normal psychomotor development during the first 6-18 months of life. Thereafter, they enter a short period of developmental stagnation followed by a rapid regression in language and motor development. Purposeful hand use is often lost and replaced by repetitive, stereotypic movements. Rett syndrome (RTT) is an X-linked dominant disorder caused frequently by mutations in the methyl-CpG-binding protein 2 gene (MECP2). The aim of this study was to search for mutations in MECP2 gene in two Tunisian patients affected with RTT. The results of mutation analysis revealed mutations in exon 4 of MECP2 gene in the two patients. In one patient we identified a new mutation consisting of a deletion of four bases (c.810-813delAAAG), which led to a frame shift and generated a premature stop codon (p.Lys271Arg fs X15) in transcriptional repression domain-nuclear localization signal (TRD-NLS) domain of MeCP2 protein. With regard to the second patient, a previously described transition (c.916C>T) that changed an arginine to a cysteine residue (p.R306C) in TRD domain of MeCP2 protein was revealed. In conclusion, a new and a known de novo mutation in MECP2 gene were revealed in two Tunisian patients affected with RTT.