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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.

journal_name

Cell

journal_title

Cell

authors

Gennarino VA,Palmer EE,McDonell LM,Wang L,Adamski CJ,Koire A,See L,Chen CA,Schaaf CP,Rosenfeld JA,Panzer JA,Moog U,Hao S,Bye A,Kirk EP,Stankiewicz P,Breman AM,McBride A,Kandula T,Dubbs HA,Macintosh R,Cardamone M

doi

10.1016/j.cell.2018.02.006

subject

Has Abstract

pub_date

2018-02-22 00:00:00

pages

924-936.e11

issue

5

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(18)30150-8

journal_volume

172

pub_type

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