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Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor
Author(s) -
Webb Bryn D.,
Evans Anthony,
Naidich Thomas P.,
Bird Lynne M.,
Parikh Sumit,
Fernandez Garcia Meilin,
Henderson Lindsay B.,
Millan Francisca,
Si Yue,
Brennand Kristen J.,
Hung Peter,
Rucker Janet C.,
Wheeler Patricia G.,
Schadt Eric E.
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24201
Subject(s) - hypotonia , proband , haploinsufficiency , biology , ataxia , cerebellum , loss function , genetics , exome sequencing , cerebellar ataxia , endocrinology , neuroscience , mutation , phenotype , gene
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.