Relevance to Autism

Two de novo loss-of-function variants and several de novo missense variants in the CTCF gene have been identified in ASD probands from the Simons Simplex Collection, the MSSNG cohort, and the SPARK cohort (Iossifov et al., 2014; Krumm et al., 2015; Zhou et al., 2022). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368). Konrad et al., 2019 found that 39 individuals with CTCF variants presented with a variable neurodevelopmental disorder frequently characterized by feeding difficulties/failure to thrive, developmental delay/intellectual disability, and behavioral abnormalities, including autism and autistic features. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified CTCF as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene is a member of the BORIS + CTCF gene family and encodes a transcriptional regulator protein with 11 highly conserved zinc finger (ZF) domains. This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. Depending upon the context of the site, the protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. If the protein is bound to a transcriptional insulator element, it can block communication between enhancers and upstream promoters, thereby regulating imprinted expression.

External Links

References