Further evidence of involvement of TMEM132E in autosomal recessive nonsyndromic hearing impairment

Abstract

Autosomal-recessive (AR) nonsyndromic hearing impairment (NSHI) displays a high degree of genetic heterogeneity with >100 genes identified. Recently, TMEM132E, which is highly expressed in inner hair cells, was suggested as a novel ARNSHI gene for DFNB99. A missense variant c.1259G>A: p.(Arg420Gln) in TMEM132E was identified that segregated with ARNSHI in a single Chinese family with two affected members. In the present study, a family of Pakistani origin with prelingual profound sensorineural hearing impairment displaying AR mode of inheritance was investigated via exome and Sanger sequencing. Compound heterozygous variants c.382G>T: p.(Ala128Ser) and c.2204C>T: p.(Pro735Leu) in TMEM132E were observed in affected but not in unaffected family members. TMEM132E variants identified in this and the previously reported ARNSHI family are located in the extracellular domain. In conclusion, we present a second ARNSHI family with TMEM132E variants which strengthens the evidence of the involvement of this gene in the etiology of ARNSHI.

Fig. 1

Pedigree diagram, sequence chromatogram, and audiograms of family DEM4877. a DEM4877 pedigree drawings and segregations results for TMEM132E variants c.382G>T: p.(Ala128Ser) and c.2204C>T: p.(Pro735Leu). Squares represent males and circles females; filled symbols denote hearing impaired individuals and clear symbols unaffected family members. Double lines indicate consanguineous marriages. b Sequencing chromatogram of TMEM132E compound heterozygous variants c.382G>T: p.(Ala128Ser) (upper panel) and c.2204C>T: p.(Pro735Leu) (lower panel) of affected individual IV:2 from family DEM4877. c The domain architecture of the TMEM132 protein family (predicted by Sanchez-Pulido and Chris P. Ponting, 2018) (upper panel) and predicted transmembrane helices in TMEM132E (adapted from the result of TMHMM 2.0 analysis) (lower panel) showing the positions of previously reported one missense p.(Arg420Gln) variant mapped on BIG2 domain, a novel variants p.(Ala128Ser) located in the conserved region (CR) and another variant p.(Pro735Leu) lies in the BIG3 domain. The previously reported and new ARNSHI variants located in the extracellular region of TMEM132E. Variants in the box were identified in this study. d–f Displays the pure tone audiograms (bone conduction audiometry can be found in Supplementary Fig. 1) for affected individuals d IV:2, e IV:3, and f V:1, respectively

Fig. 2

Predicted three-dimensional structure of TMEM132E. a Ball and stick model representation of p.Ala128 and p.Pro735 residues were highlighted by red and blue square respectively while b–e showing the interaction pattern of amino acid residues. b p.Ala128 (wild type), c p.Ser128 (mutant), d p.Pro735 (wild type) and e p.Leu735 (mutant)