MPZL2—A common autosomal recessive deafness gene related to moderate sensorineural hearing loss in the Chinese population

Abstract

Background: Mutations in MPZL2, the characteristic genetic etiology of autosomal recessive deafness loci 111 (DFNB111), cause non-syndromic and moderate sensorineural hearing loss. Methods: In this study, we analyzed the phenotype and genotype of 8 pedigrees consisting of 10 deaf patients with bi-allelic pathogenic or likely pathogenic variants in MPZL2. These patients were identified from a 3272 Chinese patient cohort who underwent genetic testing. Results: Apart from symmetrical and moderate sensorineural hearing loss, the MPZL2-related phenotype was characterized by progressive hearing loss with variation in the onset age (congenital defect to onset at the young adult stage). We determined that in the Chinese population, the genetic load of MPZL2 defects was 0.24% (8/3272) in patients diagnosed with hearing loss and 13.11% (8/61) in patients diagnosed with hereditary moderate sensorineural hearing loss caused by STRC, OTOA, OTOG, OTOGL, TECTA, and MPZL2 variants. Three known MPZL2 variants (c.220C>T (p.Gln74*), c.68delC (p.Pro23Leufs*2), c.463delG (p.Ala155Leufs*10)) and a novel start loss variant (c.3G>T (p.Met1?)) were identified. A 3D model of wild type and mutants of myelin protein zero-like 2 (MPZL2) was constructed and spatial structure analysis revealed that mutational susceptibility in the signal peptide domain might be explained by the instability of the loop structure. By allele frequency analysis, MPZL2 c.220C>T was identified as the hotspot variant in the Chinese population and even in East Asia compared with c.72delA (p.Ile24Metfs*22) in European and West Asia. Conclusions: We concluded that apart from moderate HL, progressive HL is another character of MPZL2-related HL, although no specified variant was verified for the progression of HL, and the penetrance and expressivity cannot be determined yet. A novo MPZL2 variant at the start codon was identified which enriched the variant spectrum of MPZL2. The hotspot variants of MPZL2 vary in different ethnicities. This study provides valuable data for the diagnosis, prognosis evaluation and genetic counseling of patients with moderate sensorineural hearing loss related to MPZL2.

Functional studies of deafness-associated pendrin and prestin variants

“…The importance of the conserved residues in TM9, TM10, and the linker portion connecting these two helices (Fig. 1B) is suggested by the presence of multiple clustered missense variants identified in these regions: p. (Albert et al, 2006;Blons et al, 2004;Carvalho et al, 2018;Chai et al, 2013;Chen et al, 2007;Choi et al, 2009;Courtmans et al, 2007;Coyle et al, 1998;Elsayed and Al-Shamsi, 2022;Gonzalez Trevino et al, 2001;Huang et al, 2018;Hutchin et al, 2005;Ji et al, 2009;Koohiyan et al, 2021;Ladsous et al, 2014;Landa et al, 2013;Miyagawa et al, 2014;Park et al, 2003;Pera et al, 2008b;Reardon et al, 2000;Rendtorff et al, 2013;Sakuma et al, 2016;Sloan-Heggen et al, 2016;Turner et al, 2019;Van Hauwe et al, 1998;Wang et al, 2007;Wasano et al, 2020;Wen et al, 2019;Wu et al, 2005;Yuan et al, 2009;Zhao et al, 2014). Among them, p.E384G, p.N392Y, p.S399P, p.R409H, p.T410K, p.T410M, p.Q413R, p.Q413P, and p.T416P were functionally characterized and found to significantly impair the anion transport function of pendrin in previous studies by us and others (Choi et al, 2009;de Moraes et al, 2016;Gillam et al, 2005;Ishihara et al, 2010;Pera et al, 2008a;Scott et al, 2000;Taylor et al, 2002;Wasano et al, 2020;…”