Publication

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

DOOFNL Consortium, Jan-2019, In : HUMAN GENETICS. 138, 1, p. 61-72 12 p.

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  • DOOFNL Consortium

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.

Original languageEnglish
Pages (from-to)61-72
Number of pages12
JournalHUMAN GENETICS
Volume138
Issue number1
Publication statusPublished - Jan-2019

    Keywords

  • POINT MUTATION, GENE, DEAFNESS, PMCA2, MOUSE, MYO6, PUMP, PHENOTYPE, INTERACTS, ISOFORM-2

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