A de novo missense variant that was predicted to be damaging was identified in the CNOT1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A recurrent missense variant in CNOT1 (p.Arg535Cys) has been found to result in holoprosencephaly-12 with or without pancreatic agenesis, a developmental disorder characterized by abnormal separation of the embryonic forebrain resulting in dysmorphic facial features and often, but not always, impaired neurologic development (Kruszka et al., 2019; De Franco et al., 2019). Vissers et al., 2020 reported on 39 individuals with CNOT1 variants (34 previously unreported cases and the 5 cases previously described in Kruszka et al., 2019 and De Franco et al., 2019) who presented with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems; of the 32 individuals assessed for behavioral abnormalities, 9 presented with autism spectrum disorder.
Molecular Function
Scaffolding component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Its scaffolding function implies its interaction with the catalytic complex module and diverse RNA-binding proteins mediating the complex recruitment to selected mRNA 3'UTRs. Involved in degradation of AU-rich element (ARE)-containing mRNAs probably via association with ZFP36. Mediates the recruitment of the CCR4-NOT complex to miRNA targets and to the RISC complex via association with TNRC6A, TNRC6B or TNRC6C. Acts as a transcriptional repressor. Represses the ligand-dependent transcriptional activation by nuclear receptors. Involved in the maintenance of embryonic stem (ES) cell identity.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development
Holoprosencephaly 12 with or without pancreatic ag
De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay
