TY - JOUR
T1 - PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features
AU - Khalil, Raida
AU - Kenny, Connor
AU - Hill, R. Sean
AU - Mochida, Ganeshwaran H.
AU - Nasir, Ramzi
AU - Partlow, Jennifer N.
AU - Barry, Brenda J.
AU - Al-Saffar, Muna
AU - Egan, Chloe
AU - Stevens, Christine R.
AU - Gabriel, Stacey B.
AU - Barkovich, A. James
AU - Ellison, Jay W.
AU - Al-Gazali, Lihadh
AU - Walsh, Christopher A.
AU - Chahrour, Maria
N1 - Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
KW - autism spectrum disorder
KW - intellectual disability
KW - neurogenetics
KW - proteasome
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U2 - 10.1002/ajmg.b.32688
DO - 10.1002/ajmg.b.32688
M3 - Article
C2 - 30421579
AN - SCOPUS:85056421109
SN - 1552-4841
VL - 177
SP - 736
EP - 745
JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
IS - 8
ER -