De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment

Jeroen J Smits ,Liselotte J C Rotteveel ,Jolien S Klein Wassink-Ruiter ,Margit Schraders ,Paul Merkus ,Wouter Koole ,Ronald J.e Pennings ,Jaap Oostrik ,Andy J Beynon ,Sarina G Kant ,Helger G Yntema ,Saskia M Maas ,Cornelis P Lanting ,R.j.c Admiraal ,Rolien Free ,P A M De Koning Gans ,Ilse Feenstra ,Jiddeke Van De Kamp ,Hannie Kremer

doi:10.1007/s00439-018-1965-1

Abstract

ATP2B2 encodes the PMCA2 Ca2+ pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca2+ from the stereocilia to the endolymph. Several mouse models have been described for this gene; mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment. Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2. Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo. Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment. After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3–6 years. Subjects had no balance complaints and vestibular testing did not yield abnormalities. There was no evidence for retrocochlear pathology or structural inner ear abnormalities. Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2.

Highlights

Hearing impairment (HI) is an important cause of social burden worldwide (WHO 2008)
This variant was not associated with autosomal dominant HI as it was inherited from the unaffected mother
Several heterozygous missense and truncating defects of the mouse ortholog of ATP2B2 were associated with early onset, progressive high-frequency HI (Bortolozzi et al 2010; Carpinelli et al 2013; Kozel et al 1998; McCullough and Tempel 2004; Spiden et al 2008; Street et al 1998; Takahashi and Kitamura 1999; Tsai et al 2006; Watson and Tempel 2013; Xu et al 2011)

Summary

Introduction

Human Genetics (2019) 138:61–72 et al 2017). It is estimated that early onset sensorineural HI (SNHI) is hereditary in about 50% of the cases and in 20% of the cases nonsyndromic SNHI is inherited in an autosomal dominant pattern (Smith et al 2005). More than 60 loci and 37 genes have been identified for autosomal dominant nonsyndromic SNHI (Hereditary Hearing loss Homepage). For many subjects with congenital or childhood-onset HI, a genetic diagnosis cannot be provided (Zazo Seco et al 2017). For several of the genes (recently) described to be associated with early onset HI, defects have so far been found in only a few or one single family. Mouse models have contributed such evidence for several genes and have been of great significance by providing candidate genes for HI in humans (Brown et al 2008; Friedman et al 2007; Wesdorp et al 2018)

Methods

Results

Conclusion