2. Academic Validation
  3. Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

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.
Bryn D Webb 1,  Anthony Evans 1,  Thomas P Naidich 2,  Lynne M Bird 3,  Sumit Parikh 4,  Meilin Fernandez Garcia 5,  Lindsay B Henderson 6,  Francisca Millan 6,  Yue Si 6,  Kristen J Brennand 1 5,  Peter Hung 2,  Janet C Rucker 7 8,  Patricia G Wheeler 9,  Eric E Schadt 1
Affiliations

Affiliations

  • 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 2 Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 3 Department of Pediatrics, University of California San Diego, Rady Children's Hospital, San Diego, California, USA.
  • 4 Neurometabolism & Neurogenetics, Cleveland Clinic, Cleveland, Ohio, USA.
  • 5 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 6 GeneDx, Gaithersburg, Maryland, USA.
  • 7 Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
  • 8 Department of Ophthalmology, New York University Grossman School of Medicine, New York, New York, USA.
  • 9 Division of Genetics, Arnold Palmer Hospital, Orlando, Florida, USA.
PMID: 33783914 DOI: 10.1002/humu.24201
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.

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