PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features
Open accessAbstract
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.
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These variants affect the protein levels of proteasome subunits, or decrease their incorporation into 20S and 26S proteasome and also the assembly of 20S and 26S proteasome.
“These variants affect the protein levels of proteasome subunits, or decreases their incorporation into 20S and 26S proteasome and also the assembly of 20S and 26S proteasome [18–20, 22, 23].”
From PSMC5 insufficiency and P320R mutation impair proteasome function (2024) · cites this paper as [23]
The Results (page unavailable) report that a PSMD12 nonsense variant reduces PSMD12 protein expression. The Discussion (page unavailable) says PSMD12 is required for proper proteasome assembly, but the paper does not show that these variants decrease subunit incorporation into, or assembly of, both 20S and 26S proteasomes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNonsense or missense variants of proteasome subunits PSMB1, PSMC3, and PSMD12 are associated with neurodevelopmental disorders.
“Previous published work has shown that nonsense or missense variants of proteasome subunits PSMB1 [18], PSMC3 [19, 20], and PSMD12 [22, 23] are associated with neurodevelopmental disorders.”
From PSMC5 insufficiency and P320R mutation impair proteasome function (2024) · cites this paper as [23]
Mutations in genes encoding proteasome subunits result in neurodevelopmental disorders, as exemplified by variants in PSMB1, PSMC3, and PSMD12.
“Furthermore, mutations in genes encoding proteasome subunits result in neurodevelopmental disorders, as exemplified by variants of genes encoding the 20S CP subunit PSMB1 (β1) [18] and the 19S RP subunits PSMC3 [19, 20] and PSMD12 [21–23].”
From PSMC5 insufficiency and P320R mutation impair proteasome function (2024) · cites this paper as [23]
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References 43 · Cited by 39
- Authors
- Khalil, R., Kenny, C., Hill, R. S., Mochida, G. H., Nasir, R., Partlow, J. N., Barry, B. J., Al‐Saffar, M., Egan, C., Stevens, C. R., Gabriel, S. B., Barkovich, A. J., Ellison, J. W., Al‐Gazali, L., Walsh, C. A., & Chahrour, M. H.
- Affiliations
- Philadelphia University (JO)
- Boston Children's Hospital (US)
- Royal Free London NHS Foundation Trust (GB)
- Broad Institute (US)
- University of California, San Francisco (US)
- The Permanente Medical Group San Francisco California
- United Arab Emirates University (AE)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Chahrour, Maria H.
- ORCID
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2018-11-13
- Volume
- 177
- Issue
- 8
- Pages
- 736-745
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- PMC
- PMC6261799
- OpenAlex
- W2901968139
- Cited by
- 39
- References
- 43
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 3 · 2020: 3
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Brain and Behavior Research Foundation (NARSAD Young Investigator Grant)
- National Institute of Mental Health (R01MH083565, RC2MH089952)
- University of Texas Southwestern Medical Center
- Howard Hughes Medical Institute
- Manton Center for Orphan Disease Research, Boston Children's Hospital
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- haploinsufficiency, neurodevelopmental disorders, autism spectrum disorder, intellectual disability, ubiquitin-proteasome system, nonsense mutation, de novo mutations, periventricular nodular heterotopia, multiplex families, phenotypic heterogeneity
- MeSH terms
- Autism Spectrum Disorder, Exome Sequencing, Adolescent, Adult, Autistic Disorder, Child, Child, Preschool, Family, Female, Humans, Male, Intellectual Disability, Mutation, Pedigree, Genetic Predisposition to Disease, Siblings, Proteasome Endopeptidase Complex, Haploinsufficiency, Neurodevelopmental Disorders
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