Alternative titles; symbols
HGNC Approved Gene Symbol: H4C6
Cytogenetic location: 6p22.2 Genomic coordinates (GRCh38): 6:26,240,393-26,240,793 (from NCBI)
For background information on histones, histone gene clusters, and the H4 histone family, see HIST1H4A (602822).
Albig et al. (1991) identified a gene encoding a member of the H4 class of histones. Albig and Doenecke (1997) designated this gene H4/c.
By genomic sequence analysis, Marzluff et al. (2002) identified the mouse and human HIST1H4F genes. All mouse and human H4 genes, including HIST1H4F, encode the same protein.
By analysis of a YAC contig, Albig et al. (1997) mapped the H4/c gene to chromosome 6p21.3, within a cluster of 35 histone genes.
By genomic sequence analysis, Marzluff et al. (2002) determined that the histone gene cluster on chromosome 6p22-p21, which they called histone gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H4F.
See HIST1H4A (602822) for functional information on H4 histones.
Associations Pending Confirmation
For discussion of a possible association between variation in the H4C6 gene and Tessadori-Bicknell-van Haaften neurodevelopmental syndrome (see 619758), see 602824.0001.
This variant is classified as a variant of unknown significance because its contribution to Tessadori-Bicknell-van Haaften neurodevelopmental syndrome (see 619758) has not been confirmed.
In a 13-year-old boy (P25) with a neurodevelopmental disorder, Tessadori et al. (2022) identified a de novo heterozygous c.283G-A transition (c.283G-A, NM_003540.4) in the H4C6 gene, resulting in a gly95-to-arg (G95R) substitution at a conserved residue in the C-terminal domain. The variant, which was found by exome sequencing, was not present in the gnomAD database. Expression of the mutation in zebrafish embryos induced severe developmental defects, suggesting that it is pathogenic. The authors postulated a dominant effect. The patient had poor overall growth, speech delay, and difficulties in school, requiring special education. Other features included dysmorphic facial features with hypertelorism and agenesis of the mandibular incisors, feeding difficulties, postaxial polydactyly of the hands, toe syndactyly, and astigmatism. Brain imaging showed a thin corpus callosum. The authors also referred to this mutation as GLY94ARG (G94R), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.
Albig, W., Doenecke, D. The human histone gene cluster at the D6S105 locus. Hum. Genet. 101: 284-294, 1997. [PubMed: 9439656] [Full Text: https://doi.org/10.1007/s004390050630]
Albig, W., Kardalinou, E., Drabent, B., Zimmer, A., Doenecke, D. Isolation and characterization of two human H1 histone genes within clusters of core histone genes. Genomics 10: 940-948, 1991. [PubMed: 1916825] [Full Text: https://doi.org/10.1016/0888-7543(91)90183-f]
Albig, W., Kioschis, P., Poustka, A., Meergans, K., Doenecke, D. Human histone gene organization: nonregular arrangement within a large cluster. Genomics 40: 314-322, 1997. [PubMed: 9119399] [Full Text: https://doi.org/10.1006/geno.1996.4592]
Marzluff, W. F., Gongidi, P., Woods, K. R., Jin, J., Maltais, L. J. The human and mouse replication-dependent histone genes. Genomics 80: 487-498, 2002. [PubMed: 12408966]
Tessadori, F., Duran, K., Knapp, K., Fellner, M., Deciphering Developmental Disorders Study, Smithson, S., Beleza Meireles, A., Elting, M. W., Waisfisz, Q., O'Donnell-Luria, A., Nowak, C., Douglas, J., and 54 others. Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome. Am. J. Hum. Genet. 109: 750-758, 2022. [PubMed: 35202563] [Full Text: https://doi.org/10.1016/j.ajhg.2022.02.003]