TBL1Y: a new gene involved in syndromic hearing loss

Abstract

Hereditary hearing loss (HHL) is an extremely heterogeneous disorder with autosomal dominant, recessive, and X-linked forms. Here, we described an Italian pedigree affected by HHL but also prostate hyperplasia and increased ratio of the free/ total PSA levels, with the unusual and extremely rare Y-linked pattern of inheritance. Using exome sequencing we found a missense variant (r.206A>T leading to p.Asp69Val) in the TBL1Y gene. TBL1Y is homologous of TBL1X, whose partial deletion has described to be involved in X-linked hearing loss. Here, we demonstrate that it has a restricted expression in adult human cochlea and prostate and the variant identified induces a lower protein stability caused by misfolded mutated protein that impairs its cellular function. These findings indicate that TBL1Y could be considered a novel candidate for HHL.

A strategic research alliance: Turner syndrome and sex differences

“…Genetic sequencing of a family with X-linked inheritance of late-onset sensorineural deafness identified a causal loss-of-function mutation in TBL1X (Bassi et al, 1999). Another family, this time with a Y-linked inheritance pattern of hearing loss, was found to have a loss-of-function mutation in TBL1Y, the Y homolog of TBL1X (Di Stazio et al, 2018). This is in contrast to a different family in which Y-linked hearing loss was associated with transposition of a region of chromosome 1 previously implicated in hearing impairment to the Y chromosome (Wang et al, 2013).…”

“…This is in contrast to a different family in which Y-linked hearing loss was associated with transposition of a region of chromosome 1 previously implicated in hearing impairment to the Y chromosome (Wang et al, 2013). Available evidence points to the potential for functional redundancy of TBL1X and TBL1Y: both genes are expressed in the human cochlea, and in vitro studies show that they bind to the same transcriptional corepressor complex and have similar effects on gene expression (Di Stazio et al, 2018; Guenther et al, 2000). Previously, it was reported that a recurrent Y chromosome deletion encompassing TBL1Y and several other genes had “no major deleterious effects”, which cast doubt on whether TBL1X/TBL1Y could contribute to phenotypes in TS (Jobling et al, 2007).…”

“…There are also clues that TBL1X/Y may be involved in sex differences in hearing loss. TBL1Y is expressed three times higher than TBL1X in the human cochlea, raising the possibility of a sex difference in TBL1 activity in the inner ear (Di Stazio et al, 2018). Interestingly, several large studies have found that hearing loss, especially at high frequencies, is more prevalent in men compared to women (Gates, Cooper, Kannel, & Miller, 1990; Helzner et al, 2005; Moller, 1981).…”

Growth factor and receptor malfunctions associated with human genetic deafness

“…They are important for ear development and hearing. 91,92 TBL1X and TBL1Y are components of nuclear receptor co-repressor (NCOR) complex which is required for tri-iodothyronine (T3)-regulated gene expression. 93 This regulation is important since thyroid hormone T3 and its receptor THRB play a role in cochlear development by controlling expression of genes necessary for hearing, which include KCNQ4 and SLC26A5.…”

“…TBL1X and TBL1Y are members of WD40 repeat‐containing protein family and act as repressors of nuclear hormone receptors. They are important for ear development and hearing . TBL1X and TBL1Y are components of nuclear receptor co‐repressor (NCOR) complex which is required for tri‐iodothyronine (T3)‐regulated gene expression .…”