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

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

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
Case Reports

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

Bryn D Webb et al. Hum Mutat. 2021 Jun.

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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Conflict of interest statement

Conflict of Interest Statement:

LBH, FM, and YS are employees of GeneDx, Inc. EES is an employee of Sema4, and BDW is a consultant for Sema4. The remainder of the authors have no conflicts to disclose.

Figures

Figure 1.
Figure 1.. Serial MRI studies of Proband 4.
(A-C). Axial T2-Weighted (T2W) MRI sections through the caudal medulla. The inferior olivary nuclei show prominent symmetrical signal increase at age 11.2 months (A) and age 11.0 years (B) that fades by age 16.4 years (C). Progressive enlargement of the cerebellar fissures indicates concurrent atrophy of both inferior cerebellar hemispheres. D-E. Axial T2W sections through the superior cerebellum at age 11.2 months (D) and 13 years (E) show symmetrical thin caliber of the superior cerebellar peduncles and increased size of the superior cerebellar fissures confirming bilateral superior cerebellar atrophy.
Figure 2.
Figure 2.. Serial mid-sagittal T1-W MRI through the vermis of Proband 4.
(A). At age 11.2 months, the anterior lobe of the vermis is normal. (B-D). T1-WMRI at ages 11 years (B), 13 years (C), and 22 years 11 months (D) show progressive vermian atrophy. See Supp. Figure S3 and Supp.Table S2.
Figure 3.
Figure 3.. Transactivation of POU4F1 p.Gln306Arg is reduced compared to wild-type.
The relative transcriptional activity (Firefly luciferase/Renilla luciferase) for POU4F1 wild-type (POU4F1-wt) and mutant (POU4F1-Q306R) was measured as described. Means ± standard deviations are shown. Significance was determined by a two tailed student t-test, ***p<0.005.
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