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Am J Med Genet B Neuropsychiatr Genet. 2018 Dec;177(8):736-745. doi: 10.1002/ajmg.b.32688. Epub 2018 Nov 13.

PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features.

Author information

1
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas.
2
Department of Biotechnology and Genetic Engineering, University of Philadelphia, Amman, Jordan.
3
Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.
4
Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.
5
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
6
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.
7
Royal Free London NHS Foundation Trust, London, United Kingdom.
8
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts.
9
Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
10
Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
11
Benioff Children's Hospital, Departments of Radiology, Pediatrics, Neurology, and Neurological Surgery, University of California San Francisco, San Francisco, California.
12
The Permanente Medical Group, San Francisco, California.
13
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
14
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas.

Abstract

Protein homeostasis is tightly regulated by the ubiquitin proteasome pathway. Disruption of this pathway gives rise to a host of neurological disorders. Through whole exome sequencing (WES) in families with neurodevelopmental disorders, we identified mutations in PSMD12, a core component of the proteasome, underlying a neurodevelopmental disorder with intellectual disability (ID) and features of autism spectrum disorder (ASD). We performed WES on six affected siblings from a multiplex family with ID and autistic features, the affected father, and two unaffected mothers, and a trio from a simplex family with one affected child with ID and periventricular nodular heterotopia. We identified an inherited heterozygous nonsense mutation in PSMD12 (NM_002816: c.367C>T: p.R123X) in the multiplex family and a de novo nonsense mutation in the same gene (NM_002816: c.601C>T: p.R201X) in the simplex family. PSMD12 encodes a non-ATPase regulatory subunit of the 26S proteasome. We confirm the association of PSMD12 with ID, present the first cases of inherited PSMD12 mutation, and demonstrate the heterogeneity of phenotypes associated with PSMD12 mutations.

KEYWORDS:

autism spectrum disorder; intellectual disability; neurogenetics; proteasome

PMID:
30421579
PMCID:
PMC6261799
[Available on 2019-12-01]
DOI:
10.1002/ajmg.b.32688

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