Unknown

Dataset Information

0

A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.


ABSTRACT: 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 ?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.

SUBMITTER: Gennarino VA 

PROVIDER: S-EPMC5832058 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.

Gennarino Vincenzo A VA   Palmer Elizabeth E EE   McDonell Laura M LM   Wang Li L   Adamski Carolyn J CJ   Koire Amanda A   See Lauren L   Chen Chun-An CA   Schaaf Christian P CP   Rosenfeld Jill A JA   Panzer Jessica A JA   Moog Ute U   Hao Shuang S   Bye Ann A   Kirk Edwin P EP   Stankiewicz Pawel P   Breman Amy M AM   McBride Arran A   Kandula Tejaswi T   Dubbs Holly A HA   Macintosh Rebecca R   Cardamone Michael M   Zhu Ying Y   Ying Kevin K   Dias Kerith-Rae KR   Cho Megan T MT   Henderson Lindsay B LB   Baskin Berivan B   Morris Paula P   Tao Jiang J   Cowley Mark J MJ   Dinger Marcel E ME   Roscioli Tony T   Caluseriu Oana O   Suchowersky Oksana O   Sachdev Rani K RK   Lichtarge Olivier O   Tang Jianrong J   Boycott Kym M KM   Holder J Lloyd JL   Zoghbi Huda Y HY  

Cell 20180201 5


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-ass  ...[more]

Similar Datasets

| S-EPMC135639 | biostudies-literature
| S-EPMC5630163 | biostudies-literature
| S-EPMC6368664 | biostudies-literature
| S-EPMC3618980 | biostudies-literature
| S-EPMC5405358 | biostudies-literature
| S-EPMC4022362 | biostudies-literature
| S-EPMC4786408 | biostudies-literature
| S-EPMC7262739 | biostudies-literature
| S-EPMC3622046 | biostudies-literature
| S-EPMC6218634 | biostudies-literature