1. Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor
- Author
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Webb, Bryn D, Evans, Anthony, Naidich, Thomas P, M Bird, Lynne, Parikh, Sumit, Fernandez Garcia, Meilin, Henderson, Lindsay B, Millan, Francisca, Si, Yue, Brennand, Kristen J, Hung, Peter, Rucker, Janet C, Wheeler, Patricia G, and Schadt, Eric E
- Subjects
Adult ,Male ,Clinical Sciences ,Haploinsufficiency ,Young Adult ,Rare Diseases ,intention tremor ,Clinical Research ,Tremor ,Exome Sequencing ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Preschool ,Retrospective Studies ,Genetics & Heredity ,Transcription Factor Brn-3A ,screening and diagnosis ,ataxia ,Neurosciences ,POU4F1 ,Syndrome ,Magnetic Resonance Imaging ,United States ,Brain Disorders ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,paroxysmal tonic upgaze ,Mutation ,Neurological ,Muscle Hypotonia ,Female ,Missense - 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.
- Published
- 2021