Alternative titles; symbols
HGNC Approved Gene Symbol: H1-4
SNOMEDCT: 1304277005;
Cytogenetic location: 6p22.2 Genomic coordinates (GRCh38) : 6:26,156,329-26,157,115 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.2 | Rahman syndrome | 617537 | Autosomal dominant | 3 |
The HIST1H1E gene encodes histone H1.4. In humans, H1.4 is one of 11 H1 linker histones that mediate the formation of higher-order chromatin structures and regulate the accessibility of regulatory proteins, chromatin remodeling factors, and histone-modifying enzymes to their target sites (summary by Tatton-Brown et al., 2017).
For background information on histones, histone gene clusters, and the H1 histone family, see HIST1H1A (142709).
Albig et al. (1991) identified a gene encoding a member of the H1 class of histones and designated it H1.4.
See HIST1H1A (142709) for functional information on H1 histones.
By in situ hybridization, Tanguay et al. (1987) mapped the histone H1.4 gene to chromosome 12q11-q21. On the other hand, Albig et al. (1993) mapped 6 H1 genes, including H1.4, to chromosome 6p22.1-p21.1. By analysis of a YAC contig, Albig et al. (1997) mapped the H1.4 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 HIST1H1E.
In 5 unrelated patients with Rahman syndrome (RMNS; 617537), Tatton-Brown et al. (2017) identified 3 different heterozygous truncating mutations in the HIST1H1E gene (142220.0001-142220.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, occurred de novo in 4 families; parental DNA from the fifth family was not available. The mutations were not found in the ExAC database or in an in-house database of 11,677 exomes. All of the mutations resulted in the generation of a similar protein truncated in the C-terminal domain, which is involved in chromatin binding and protein-protein interactions. The truncated proteins were predicted to have a reduced net charge compared to the wildtype protein, rendering them likely to be less effective in neutralizing negatively charged linker DNA. Moreover, truncation of the C terminus would likely impede DNA binding and protein-protein interactions. The patients were ascertained from a cohort of 710 individuals with intellectual disability and height and/or head circumference equal to or greater than +2 SD, or 'unspecified overgrowth,' who underwent genetic studies. Functional studies of the variants and studies of patient cells were not performed.
In 2 unrelated patients (COG0405 and COG1832) with Rahman syndrome (RMNS; 617537), aged 13 and 9 years, respectively, Tatton-Brown et al. (2017) identified a de novo heterozygous 1-bp duplication (c.430dupG, NM_005321) in the HIST1H1E gene, resulting in a frameshift, premature termination, and generation of a truncated protein in the C-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in an in-house database of 11,677 exomes.
In 2 unrelated patients (COG0412 and COG0552) with Rahman syndrome (RMNS; 617537), aged 16 and 4 years, respectively, Tatton-Brown et al. (2017) identified a heterozygous 1-bp duplication (c.441dupC, NM_005321) in the HIST1H1E gene, resulting in a frameshift, premature termination, and generation of a truncated protein in the C-terminal domain. The mutation, which was found by whole-exome sequencing confirmed by Sanger sequencing, was not found in the ExAC database or in an in-house database of 11,677 exomes. The mutation occurred de novo in 1 patient; parental DNA from the other patient was not available.
In a 1.9-year-old girl (patient COG1739) with Rahman syndrome (RMNS; 617537), Tatton-Brown et al. (2017) identified a de novo heterozygous 23-bp deletion (c.436_458del23, NM_005321) in the HIST1H1E gene, resulting in a frameshift, premature termination, and generation of a truncated protein in the C-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in an in-house database of 11,677 exomes.
Albig, W., Drabent, B., Kunz, J., Kalff-Suske, M., Grzeschik, K.-H., Doenecke, D. All known human H1 histone genes except the H1(0) gene are clustered on chromosome 6. Genomics 16: 649-654, 1993. [PubMed: 8325638] [Full Text: https://doi.org/10.1006/geno.1993.1243]
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]
Tanguay, R. M., Berube, D., Gagne, R. Localization of histone genes to chromosomes 6, 12, and 1 by in situ hybridization. (Abstract) Cytogenet. Cell Genet. 46: 702 only, 1987.
Tatton-Brown, K., Loveday, C., Yost, S., Clarke, M., Ramsay, E., Zachariou, A., Elliott, A., Wylie, H., Ardissone, A., Rittinger, O., Stewart, F., Temple, I. K., Cole, T., Childhood Overgrowth Collaboration, Mahamdallie, S., Seal, S., Ruark, E., Rahman, N. Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability. Am. J. Hum. Genet. 100: 725-736, 2017. [PubMed: 28475857] [Full Text: https://doi.org/10.1016/j.ajhg.2017.03.010]