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. Twopoint 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.

The transmembrane inner ear (Tmie) protein is essential for normal hearing and balance in the zebrafish

“…It is likely that the putatively cytoplasmic region of Tmie is essential to its function. Human mutations that disrupt arginine residues there lead to profound hearing loss (23,24). This highly charged E region could serve, for example, as a site of interaction with other proteins that have a direct role in mechanotransduction.…”

Identification of novel variants in the TMIE gene of patients with nonsyndromic hearing loss

“…Mutations in the TMIE gene have been shown to cause nonsyndromic, recessively inherited hearing loss [5,9]. In the present study, we found that two novel variants (g.1-219A > T and c.257G > A) of TMIE gene in the patients are heterozygous, with one variant and one normal allele.…”

“…As a result, an altered TMIE protein leads to its loss of function. In addition, it has also been shown that variants in TMIE residues R81, R84 and R92 are associated with nonsyndromic hearing loss [5,9]. Protein phosphorylation plays a central role in many biological phenomena [24].…”

“…To date, seven mutations of TMIE have been reported to be associated with nonsyndromic hearing loss [5,9]. Of the seven different mutations that have been identified in patients with nonsyndromic hearing impairment (NSHI), two are located in the extracellular region (4-BP INS, 125CGCC and p.E31G) [5,9], three are located in the cytoplasmic region (p.R81C, p.R84W, and p.R92W) [5] and two are located in intronic regions (c.212-2A > C in intron 2 and 6-BP DEL/1-BP INS in intron 1) [5,9]. In this study, we did not detect any of the aforementioned variants; instead we identified a novel missense variant (p.R86Q) in one patient and a novel variant of the promoter region (g.1-219A > T) in another one patient with nonsyndromic hearing loss.…”

“…TMIE (NM_147196) is located on chromosome 3p21. It contains 4 exons with an open reading frame of 468 base pairs that encode 155 amino acid residues [5,9]. At least 7 mutations of TMIE have been reported to be associated with nonsyndromic hearing loss [5,9].…”