| First Author | Gennarino VA | Year | 2018 |
| Journal | Cell | Volume | 172 |
| Issue | 5 | Pages | 924-936.e11 |
| PubMed ID | 29474920 | Mgi Jnum | J:340356 |
| Mgi Id | MGI:6120327 | Doi | 10.1016/j.cell.2018.02.006 |
| Citation | Gennarino VA, et al. (2018) A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures. Cell 172(5):924-936.e11 |
| abstractText | 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 Pumilio1 (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 (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by approximately 25% in the adult-onset cases and by approximately 50% in the infantile-onset 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. |
