Relevance to Autism

De novo coding-synonymous variants in the H4C5 gene were identified in ASD probands from the Simons Simplex Collection, the Autism Sequencing Consortium, and the MSSNG cohort (Iossifov et al., 2014; Yuen et al., 2016; Satterstrom et al., 2020), while an inherited frameshift variant in this gene was observed in two ASD-affected siblings from a multiplex family in the iHART cohort (Ruzzo et al., 2019). Tessadori et al., 2022 reported individuals with de novo missense variants in the H4C5 gene presenting with a neurodevelopmental syndrome characterized by intellectual disability and developmental delay; two of these individuals also presented with autism spectrum disorder. Additional functional assessment of H4C5 missense variants in zebrafish embryos in this report demonstrated developmental defects in embryos expressing mutant H4C5 compared to wild-type protein for many of the missense variants tested, including those observed in the two individuals with autism spectrum disorder.

Molecular Function

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H4 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6.

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References