Alternative titles; symbols
HGNC Approved Gene Symbol: H4C11
Cytogenetic location: 6p22.1 Genomic coordinates (GRCh38): 6:27,824,092-27,824,480 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.1 | ?Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 2 | 619759 | Autosomal dominant | 3 |
For background information on histones, histone gene clusters, and the H4 histone family, see HIST1H4A (602822).
Heintz et al. (1981) cloned a gene, called H4/e, encoding an H4 histone.
By genomic sequence analysis, Marzluff et al. (2002) identified the mouse and human HIST1H4J genes. All mouse and human H4 genes, including HIST1H4J, encode the same protein.
By analysis of a YAC contig from 6p22-p21.3, Albig and Doenecke (1997) characterized a second cluster of 16 histone genes, including H4/e, located 2 Mb centromeric to the major histone gene cluster.
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 HIST1H4J.
See HIST1H4A (602822) for functional information on H4 histones.
In a Hispanic boy with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-2 (TEBIVANED2; 619759), Tessadori et al. (2020) identified a de novo missense mutation affecting a highly conserved residue in the HIST1H4J gene (K92E; 602826.0001). The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. Although studies of patient cells were not performed, expression of the mutation in zebrafish embryos resulted in similar developmental abnormalities (see ANIMAL MODEL). The authors concluded that the mutation would lead to defects in K92 posttranslational modification likely resulting in genomic instability with perturbation of the cell cycle, as was demonstrated in functional studies of patients with similar K92 mutations in the HIST1H4C gene (602827).
Tessadori et al. (2020) found that expression of the HIST1H4J K92E mutation in zebrafish embryos resulted in developmental defects of the head structures, brain and eyes, body axis growth, and tail, similar to features observed in the patient with the mutation.
In a 14-year-old Hispanic boy with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-2 (TEBIVANED2; 619759), Tessadori et al. (2020) identified a de novo heterozygous c.274A-G transition (chr6.27792176A-G, GRCh37) in the H4C11 gene, resulting in a lys92-to-glu (K92E) substitution at a highly conserved residue. The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. Studies of patient cells were not performed, but expression of the mutation in zebrafish embryos resulted in developmental defects of the head structures, brain and eyes, body axis growth, and tail, similar to features observed in the patient. (The authors reported this variant as LYS91GLN, stating that 'For histones, the N-terminal methionine residue incorporated during translation is excised, resulting in a -1 shift in amino acid number.')
This variant is classified as a variant of unknown significance because its contribution to Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-2 (TEBIVANED2; 619759) has not been confirmed.
In a 10-month-old boy (P29) with a neurodevelopmental disorder, Tessadori et al. (2022) identified a de novo heterozygous c.121C-T transition (c.121C-T, NM_021968.4) in the H4C11 gene, resulting in an arg41-to-cys (R41C) substitution in the core globular domain. The variant, which was found by exome sequencing, was not present in the gnomAD database. Expression of the variant in zebrafish embryos did not induce significant developmental defects compared to wildtype. Tessadori et al. (2022) stated that there were inherent limitations in the zebrafish assays. The patient had poor overall growth with microcephaly (-5.14 SD), hypotonia, feeding difficulties, global developmental delay, hypospadias, and cryptorchidism. Dysmorphic features included round face, epicanthal folds, almond-shaped eyes, upslanting palpebral fissures, broad nasal bridge, downturned corners of the mouth, and everted lower lip. The authors also referred to this mutation as ARG40CYS (R40C), 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]
Heintz, N., Zernik, M., Roeder, R. G. The structure of the human histone genes: clustered but not tandemly repeated. Cell 24: 661-668, 1981. [PubMed: 6265100] [Full Text: https://doi.org/10.1016/0092-8674(81)90092-1]
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]
Tessadori, F., Rehman, A. U., Giltay, J. C., Xia, F., Streff, H., Duran, K., Bakkers, J., Lalani, S. R., van Haaften, G. A de novo variant in the human HIST1H4J gene causes a syndrome analogous to the HIST1H4C-associated neurodevelopmental disorder. Europ. J. Hum. Genet. 28: 674-678, 2020. [PubMed: 31804630] [Full Text: https://doi.org/10.1038/s41431-019-0552-9]