Alternative titles; symbols
HGNC Approved Gene Symbol: H4C3
Cytogenetic location: 6p22.2 Genomic coordinates (GRCh38): 6:26,103,933-26,104,337 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.2 | Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 1 | 619758 | Autosomal dominant | 3 |
For background information on histones, histone gene clusters, and the H4 histone family, see HIST1H4A (602822).
By genomic sequence analysis, Marzluff et al. (2002) identified the mouse and human HIST1H4C genes. All mouse and human H4 genes, including HIST1H4C, encode the same protein.
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997) characterized a cluster of 35 histone genes, including H4/g.
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 HIST1H4C.
See HIST1H4A (602822) for functional information on H4 histones.
In 3 patients from 2 unrelated families with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-1 (TEBIVANED1; 619758), Tessadori et al. (2017) identified heterozygous missense mutations affecting a highly conserved residue in the HIST1H4C gene: K92Q (602827.0001) and K92R (602827.0002). The mutations, which were found by trio-based whole-exome sequencing, occurred de novo in 1 patient and was inherited from an unaffected father who was mosaic in the other 2 patients, who were sibs. Studies of patient fibroblasts showed that the mutant proteins were incorporated into the nucleosome, but posttranslational marks, such as acetylation and ubiquitination, on K92 were absent in the fraction of mutated histone H4 molecules. RNA-seq analysis of patient fibroblasts showed differential expression of multiple genes, including histone genes and genes involved in chromosome organization, DNA packaging, and numerous cell cycle-related genes.
Tessadori et al. (2022) identified a de novo heterozygous K91Q mutation in the H4C3 gene (602827.0001) in 3 unrelated male patients (P4-P6) with TEBIVANED1. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The variant was located in the C-terminal domain of the protein. Expression of the mutation in zebrafish embryos induced severe developmental defects, suggesting that it is pathogenic. The authors postulated a dominant effect. Three additional individuals (P1-P3) with a similar neurodevelopmental disorder were found to carry de novo heterozygous variants affecting the same conserved residue in the core globular domain (P32A and P32L). Neither variant was present in the gnomAD database. However, expression of the P32A variant in zebrafish embryos induced only some developmental defects that did not reach significance compared to wildtype; functional studies of P32L were not performed.
Tessadori et al. (2017) found that expression of the HIST1H4C K92Q and K92R mutations in zebrafish resulted in severe embryonic developmental defects, including underdeveloped brain and eyes, defective body axis growth, and a dysmorphic tail. These findings recapitulated some of the features observed in patients carrying the mutations. Analysis of mutant embryos showed an accumulation of double-stranded DNA breaks, genomic instability, increased cell apoptosis and nuclear fragmentation in the head and tail, and disrupted cell cycle progression. There was also evidence of abnormal H4K92 acetylation and ubiquitination compared to controls. The findings suggested an important role for histone H4K92 in early embryonic development.
In a 9-year-old girl (patient 1) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-1 (TEBIVANED1; 619758), Tessadori et al. (2017) identified a de novo heterozygous c.274A-C transversion in the H4C3 gene, resulting in a lys92-to-gln (K92Q) substitution at a highly conserved residue. The mutation was found by trio-based whole-exome sequencing. Analysis of patient fibroblasts showed disrupted posttranslational modifications of K92 in mutant histone H4 molecules, as well as RNA-seq evidence of differential expression of genes involved in histone dynamics and cell-cycle progression. (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.')
Tessadori et al. (2022) identified a de novo heterozygous c.274A-C transversion (c.274A-C, NM_003542.4) in the H4C3 gene resulting in a K91Q mutation in 3 unrelated male patients (P4-P6) with TEVANED1. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The variant was located in the C-terminal domain of the protein. Expression of the mutation in zebrafish embryos induced severe developmental defects, suggesting that it is pathogenic. The authors postulate a dominant effect. The patients had poor overall growth, hypotonia, global developmental delay, and dysmorphic features. Two had autism spectrum disorder.
In 2 sibs (patients 2 and 3) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-1 (TEBIVANED1; 619758), Tessadori et al. (2017) identified a heterozygous c.275A-G transition in the H4C3 gene, resulting in a lys91-to-arg (K91R) substitution at a highly conserved residue. The mutation was inherited from the unaffected father who was mosaic for the mutation. Analysis of patient fibroblasts showed disrupted posttranslational modifications of K91 in mutant histone H4 molecules, as well as RNA-seq evidence of differential expression of genes involved in histone dynamics and cell-cycle progression. Patient 3 died of multiorgan failure in early infancy. (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.')
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]
Tessadori, F., Giltay, J. C., Hurst, J. A., Massink, M. P., Duran, K., Vos, H. R., van Es, R. M., Deciphering Developmental Disorders Study, Scott, R. H., van Gassen, K. L. I., Bakkers, J., van Haaften, G. Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control. Nature Genet. 49: 1642-1646, 2017. [PubMed: 28920961] [Full Text: https://doi.org/10.1038/ng.3956]