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

Hum Genet. 2019 Jan;138(1):61-72. doi: 10.1007/s00439-018-1965-1. Epub 2018 Dec 8.


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.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers / analysis*
  • Child
  • Child, Preschool
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease*
  • Hearing Loss / genetics*
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Pedigree
  • Plasma Membrane Calcium-Transporting ATPases / genetics*
  • Prognosis
  • Young Adult


  • Biomarkers
  • Plasma Membrane Calcium-Transporting ATPases
  • ATP2B2 protein, human