Trio-exome sequencing of 745 participants with NDD and/or epilepsy from the Center for Medical Genetics of the University Hospital Antwerp in Smal et al., 2024 identified a de novo missense variant in the H3-3B gene (NM_005324.5:c.35C>T;p.Thr12Ile) in a patient presenting with autism spectrum disorder, global developmental delay, and dysmorphic features. A de novo missense variant in H3-3B had previously been identified in a male ASD proband from the SPARK cohort (Zhou et al., 2022). Heterozygous mutations in the H3-3B gene are also responsible for Bryant-Li-Bhoj neurodevelopmental syndrome 2 (OMIM 601058). A de novo missense variant (p.Ile52Asn) that was experimentally shown to significantly decrease protein expression was identified in one of the the six individuals with H3-3B variants described in Okur et al., 2021; the individual with this variant was reported to have autism. One of the twelve newly reported individuals with H3-3B variants in Carris et al., 2024 was reported to have an ASD diagnosis. Association of this gene with schizophrenia has been described in a report involviing 24 Canadian multiplex families (Manley et al., 2018) and in a Chinese case-control study (Liu et al., 2020); moreover, Manley et al., 2018 confirmed by luciferase reporter assays that the A allele of the 3'UTR SNP that associated with schizophrenia (rs1060120) significantly reduced luciferase expression, indicating a stronger interaction with miR-616, than the G allele (p = 0.000412). Co-deletion of H3.3-encoding genes H3-3A and H3-3B from newly postmitotic neurons abrogated H3.3 accumulation, markedly altered the histone posttranslational modification landscape, and caused widespread disruptions to the establishment of the neuronal transcriptome; these changes coincided with developmental phenotypes in neuronal identities and axon projections (Funk et al., 2022).
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 contains introns and its mRNA is polyadenylated, unlike most histone genes. The protein encoded by this gene is a replication-independent histone that is a member of the histone H3 family.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes
A novel iPSC model of Bryant-Li-Bhoj neurodevelopmental/neurodegenerative syndrome demonstrates the role of histone H3.3 in chromatin dynamics, neuronal differentiation, and maturation
Luciferase reporter assays demonstrated that the A allele of the 3'UTR SNP that associated with schizophrenia significantly reduced luciferase expression, indicating a stronger interaction with miR-616, than the G allele (p = 0.000412)
24 Canadian multiplex families with 85 individuals with a diagnosis of schizophrenia or chronic schi
810 Chinese schizophrenia patients recruited from Shanghai Mental Health Center during 20142018 (65.8% male, mean age 45.9 17.11 years) and 490 healthy controls (34.1% male, mean age 37.47 12.48 years).
811 Chinese schizophrenia patients recruited from Shanghai Mental Health Center during 20142018 (65.8% male, mean age 45.9 17.11 years) and 490 healthy controls (34.1% male, mean age 37.47 12.48 years).
