Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

Hum Mutat. 2021 Jun;42(6):685-693. doi: 10.1002/humu.24201. Epub 2021 Apr 15.

Abstract

De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome.

Keywords: POU4F1; ataxia; intention tremor; paroxysmal tonic upgaze.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Ataxia / complications
  • Ataxia / diagnosis
  • Ataxia / genetics*
  • Ataxia / pathology
  • Child
  • Child, Preschool
  • Exome Sequencing
  • Female
  • Haploinsufficiency
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Muscle Hypotonia / complications
  • Muscle Hypotonia / diagnosis
  • Muscle Hypotonia / genetics*
  • Mutation, Missense
  • Retrospective Studies
  • Syndrome
  • Transcription Factor Brn-3A / genetics*
  • Tremor / complications
  • Tremor / diagnosis
  • Tremor / genetics*
  • United States
  • Young Adult

Substances

  • POU4F1 protein, human
  • Transcription Factor Brn-3A