A Truncating Mutation in SERPINB6 Is Associated with Autosomal-Recessive Nonsyndromic Sensorineural Hearing Loss

Abstract

More than 270 million people worldwide have hearing loss that affects normal communication. Although astonishing progress has been made in the identification of more than 50 genes for deafness during the past decade, the majority of deafness genes are yet to be identified. In this study, we mapped a previously unknown autosomal-recessive nonsyndromic sensorineural hearing loss locus (DFNB91) to chromosome 6p25 in a consanguineous Turkish family. The degree of hearing loss was moderate to severe in affected individuals. We subsequently identified a nonsense mutation (p.E245X) in SERPINB6, which is located within the linkage interval for DFNB91 and encodes for an intracellular protease inhibitor. The p.E245X mutation cosegregated in the family as a completely penetrant autosomal-recessive trait and was absent in 300 Turkish controls. The mRNA expression of SERPINB6 was reduced and production of protein was absent in the peripheral leukocytes of homozygotes, suggesting that the hearing loss is due to loss of function of SERPINB6. We also demonstrated that SERPINB6 was expressed primarily in the inner ear hair cells. We propose that SERPINB6 plays an important role in the inner ear in the protection against leakage of lysosomal content during stress and that loss of this protection results in cell death and sensorineural hearing loss.

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

“…17 The progressive nature of SNHL, as related to SERPINB6, was proposed even though its progression has not been validated by audiograms in the literature. 17,21 Indeed, subject SB114-206, who carried SERPINB6 mutations in this study, showed significant deterioration of the hearing threshold over 2 years, which was in marked contrast to SB109-201, who possessed OTOGL mutations (Figure 1c). The age at onset of DFNB91-induced SNHL in humans has not been determined previously, but our study clearly indicates that SNHL onset occurred during the early teens, suggesting DFNB91 as a possible etiology of pediatric SNHL.…”

“…11,17 OTOGL is expressed in Claudius cells, Hensen's cells, outer hair cells, and also prominently in the three acellular gelatinous membranes (i.e., the cupula, the otoconical membrane, and the tectorial membrane). OTOGL 17,21 Alterations in this gene do not seem to contribute to congenital, prelingual, severe to profound SNHL based on the absence of mutations in this gene among a large cohort comprising such cases. 17 The progressive nature of SNHL, as related to SERPINB6, was proposed even though its progression has not been validated by audiograms in the literature.…”

Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5

“…This is also evident from three recently identified arNSHI genes, PNPT1, SERPINB6 and TSPEAR, for which mutations have only been described in a single family each. [5][6][7] Further evidence to assign a candidate gene as a deafness gene can come from animal models, especially mouse models with hearing loss. Several genes essential for hearing in humans were identified after they had already been demonstrated to be associated with deafness in mice.…”

Activation of TRAIL‐DR5 pathway promotes sensorineural degeneration in the inner ear

“…This partial and cell‐specific effect may be due to putative gradients in cochlear expression of DcR1, DcR2, or an unknown TRAIL receptor. Indeed, IHCs and OHCs are known to express different proteins – for example, prestin is expressed in OHCs only (Zheng et al ., 2000) while SERPINB6 is expressed in IHCs only (Sirmaci et al ., 2010). Alternatively, it is possible that the anti‐DR5 antibody could not completely block the function of DR5 due to the complex structure of the multilayered cochlear explants that limited the antibody's access to specific cells.…”