title: TMC1 but not TMC2 is responsible for autosomal recessive nonsyndromic hearing impairment in Tunisian families.
abstract: 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.
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Sfax, Tunisie.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Tlili
authors.forename: Imen Ben
authors.initials: IB
authors.lastname: Rebeh
authors.forename: Mounira
authors.initials: M
authors.lastname: Aifa-Hmani
authors.forename: Houria
authors.initials: H
authors.lastname: Dhouib
authors.forename: Jihen
authors.initials: J
authors.lastname: Moalla
authors.forename: Jihen
authors.initials: J
authors.lastname: Tlili-Chouchène
authors.forename: Mariem Ben
authors.initials: MB
authors.lastname: Said
authors.forename: Imed
authors.initials: I
authors.lastname: Lahmar
authors.forename: Zeineb
authors.initials: Z
authors.lastname: Benzina
authors.forename: Ilhem
authors.initials: I
authors.lastname: Charfedine
authors.forename: Nabil
authors.initials: N
authors.lastname: Driss
authors.forename: Abdelmonem
authors.initials: A
authors.lastname: Ghorbel
authors.forename: Hammadi
authors.initials: H
authors.lastname: Ayadi
authors.forename: Saber
authors.initials: S
authors.lastname: Masmoudi
mesh_terms: D000483:Alleles; D002869:Chromosome Aberrations; D018389:Codon, Nonsense; D000072259:Connexin 26; D017630:Connexins; D003241:Consanguinity; D004252:DNA Mutational Analysis; D003638:Deafness / Q000175:diagnosis / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006580:Genetic Carrier Screening; D005819:Genetic Markers / Q000235:genetics; D005828:Genetics, Population; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D014416:Tunisia
chemical_list: C408224:CEMIP2 protein, human; D018389:Codon, Nonsense; D017630:Connexins; C000607042:GJB2 protein, human; D005819:Genetic Markers; D008565:Membrane Proteins; C451751:TMC1 protein, human; D000072259:Connexin 26