title: Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment.
abstract: To date, 37 genes have been identified for nonsyndromic hearing impairment (NSHI). Identifying the functional sequence variants within these genes and knowing their population-specific frequencies is of public health value, in particular for genetic screening for NSHI. To determine putatively functional sequence variants in the transmembrane inner ear (TMIE) gene in Pakistani and Jordanian families with autosomal recessive (AR) NSHI, four Jordanian and 168 Pakistani families with ARNSHI that is not due to GJB2 (CX26) were submitted to a genome scan. Two-point and multipoint parametric linkage analyses were performed, and families with logarithmic odds (LOD) scores of 1.0 or greater within the TMIE region underwent further DNA sequencing. The evolutionary conservation and location in predicted protein domains of amino acid residues where sequence variants occurred were studied to elucidate the possible effects of these sequence variants on function. Of seven families that were screened for TMIE, putatively functional sequence variants were found to segregate with hearing impairment in four families but were not seen in not less than 110 ethnically matched control chromosomes. The previously reported c.241C>T (p.R81C) variant was observed in two Pakistani families. Two novel variants, c.92A>G (p.E31G) and the splice site mutation c.212 -2A>C, were identified in one Pakistani and one Jordanian family, respectively. The c.92A>G (p.E31G) variant occurred at a residue that is conserved in the mouse and is predicted to be extracellular. Conservation and potential functionality of previously published mutations were also examined. The prevalence of functional TMIE variants in Pakistani families is 1.7% [95% confidence interval (CI) 0.3-4.8]. Further studies on the spectrum, prevalence rates, and functional effect of sequence variants in the TMIE gene in other populations should demonstrate the true importance of this gene as a cause of hearing impairment.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Alkek N1619.01, Houston, TX 77030, USA.
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos
authors.forename: Hatem
authors.initials: H
authors.lastname: El-Shanti
authors.forename: Shaheen
authors.initials: S
authors.lastname: Sikandar
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.forename: Attya
authors.initials: A
authors.lastname: Bhatti
authors.forename: Kai
authors.initials: K
authors.lastname: Yan
authors.forename: Maria H
authors.initials: MH
authors.lastname: Chahrour
authors.forename: Nathan
authors.initials: N
authors.lastname: McArthur
authors.forename: Thanh L
authors.initials: TL
authors.lastname: Pham
authors.forename: Amjad Abdullah
authors.initials: AA
authors.lastname: Mahasneh
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D000072259:Connexin 26; D017630:Connexins; D005787:Gene Frequency; D005808:Genes, Recessive; D008040:Genetic Linkage; D014644:Genetic Variation; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D007597:Jordan; D008565:Membrane Proteins / Q000235:genetics*; D010154:Pakistan; D010375:Pedigree; D011110:Polymorphism, Genetic
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D008565:Membrane Proteins; C466299:TMIE protein, human; D000072259:Connexin 26