PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features
Year: 2018
Type: article
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.
DOI: 10.1002/ajmg.b.32688
Institutions: Philadelphia University, The University of Texas Southwestern Medical Center, Boston Children's Hospital, Manton Center for Orphan Disease Research, Harvard University, Massachusetts General Hospital, Royal Free London NHS Foundation Trust, Howard Hughes Medical Institute, United Arab Emirates University, Broad Institute, Massachusetts Institute of Technology, University of California, San Francisco, UCSF Benioff Children's Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, Brain and Behavior Research Foundation, University of Texas Southwestern Medical Center, United Arab Emirates University, National Institutes of Health, Manton Center for Orphan Disease Research, Boston Children's Hospital, National Institute of Mental Health
OpenAlex ID: W2901968139