A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures
| Autor: | Paula Morris, Rani Sachdev, Kevin Ying, Rebecca Macintosh, Kerith-Rae Dias, Holly Dubbs, Jiang Tao, Amy M. Breman, Mark J. Cowley, Oana Caluseriu, Laura M McDonell, Oksana Suchowersky, Li Wang, Berivan Baskin, Tony Roscioli, Elizabeth E. Palmer, Vincenzo A. Gennarino, Carolyn J. Adamski, Ann M. E. Bye, Chun-An Chen, Jessica A. Panzer, Michael Cardamone, Jianrong Tang, Huda Y. Zoghbi, Marcel E. Dinger, Ying Zhu, Edwin P. Kirk, Amanda Koire, J. Lloyd Holder, Megan T. Cho, Lindsay B. Henderson, Ute Moog, Lauren See, Kym M. Boycott, Tejaswi Kandula, Pawel Stankiewicz, Jill A. Rosenfeld, Shuang Hao, Olivier Lichtarge, Christian P. Schaaf, Arran McBride |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Developmental Disabilities Haploinsufficiency medicine.disease_cause Mice 0302 clinical medicine Missense mutation Age of Onset Child Genetics Neurons Aged 80 and over Mutation biology Protein Stability Neurodegeneration RNA-Binding Proteins Middle Aged Penetrance Current Literature in Basic Science Pedigree Child Preschool Female medicine.symptom Adult Ataxia Adolescent Mutation Missense Ataxin 1 General Biochemistry Genetics and Molecular Biology Article Evolution Molecular 03 medical and health sciences Seizures medicine Animals Humans Genetic Predisposition to Disease Cerebellar ataxia Base Sequence Infant medicine.disease 030104 developmental biology HEK293 Cells biology.protein 030217 neurology & neurosurgery Gene Deletion Developmental Biology |
| Zdroj: | Epilepsy Currents |
| Popis: | A Mild PUM1 Mutation Is Associated With Adult-Onset Ataxia, Whereas Haploinsufficiency Causes Developmental Delay and Seizures Gennarino VA, Palmer EE, McDonell LM, et al. Cell. 2018;172(5):924-936.e11. doi:10.1016/j.cell.2018.02.006. 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 11 individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (PUM1-associated developmental disability, ataxia, and seizure). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (PUM1-related cerebellar ataxia). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼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. |
| Databáze: | OpenAIRE |
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