期刊
CELL
卷 172, 期 5, 页码 924-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.02.006
关键词
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资金
- Howard Hughes Medical Institute (HHMI)
- National Institute of Neurological Disorders and Stroke (NINDS) [2R37NS027699, NS091381]
- National Institute of General Medical Sciences [GM066099, GM079656]
- Robbins Foundation
- Joan and Stanford Alexander Family [CPRITRP160283]
- National Ataxia Foundation/Young Investigator Research Grant
- Neuroconnectivity Core at the NRI
- Eunice Kennedy Shriver National Institute of Child Health & Human Development
- Care4Rare Canada Consortium - Genome Canada
- Canadian Institute of Health Research
- Ontario Genomics Institute
- Ontario Research Fund
- Genome Quebec
- Children's Hospital of Eastern Ontario Foundation
- NHMRC post-graduate scholarship [GNT11149630]
- NHMRC CJ Martin Overseas Post-Doctoral Fellowship [GNT0512123]
- Toupin Foundation at the University of Alberta
- Baylor College of Medicine [IDDRC U54HD083092]
Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio 1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio 1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by similar to 25% in the adult-onset cases and by similar to 50% in the in it cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.
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