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Cell. 2018 Feb 22;172(5):924-936.e11. doi: 10.1016/j.cell.2018.02.006.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: vag2138@cumc.columbia.edu.
2
Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia; Genetics of Learning Disability Service, Waratah, NSW 2298, Australia.
3
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
6
Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
8
Department of Pediatrics, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
9
Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.
10
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
11
Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia.
12
Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia; Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia.
13
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA.
14
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
15
Sydney Children's Hospital, Randwick, NSW 2031, Australia.
16
Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia.
17
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
18
GeneDx, 207 Perry Pkwy Gaithersburg, MD 20877, USA.
19
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
20
Sydney Children's Hospital, Randwick, NSW 2031, Australia; Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia; Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2031, Australia.
21
Department of Medical Genetics, University of Alberta, AB T6G 2H7, Canada.
22
Department of Medical Genetics, University of Alberta, AB T6G 2H7, Canada; Departments of Medicine (Neurology) and Pediatrics, University of Alberta, AB, Canada.
23
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hzoghbi@bcm.edu.

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.

KEYWORDS:

Ataxin-1; PADDAS; PRCA; Pumilio1; RNA-binding proteins; ataxia; chromosome 1p35.2; copy number variants; developmental delay; intellectual disability; seizures

PMID:
29474920
PMCID:
PMC5832058
[Available on 2019-02-22]
DOI:
10.1016/j.cell.2018.02.006

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