H1-4 Gene:H1-4 is a single-exon gene, encodes the H1.4 linker histone. Linker histones associate with the DNA between nucleosomes, help organize DNA as chromatin, and play a role in compacting DNA, in regulating gene expression. H1.4 linker histone has a "tripartite" structure consisting of a highly conserved globular domain and two less conserved N-terminal and C-terminal tails.
H1-4 Mutations: To date, all reported H1-4 pathogenic variants are frameshift or indel variants clustered in the C terminus. These frameshift variants, regardless the locations, result in a same tail of ~40 amnio acids (C-terminus frameshift tail, H1-4 CFT).
Mechanism of disease causation: Mutant H1-4 CFT protein is stable in patient derived IPSCs. It is hypothed that H1-4 CFT function as gain of function mechanism and disrupt the normal binding between the positively charged H1.4 linker histone and negatively charged DNA. The cells expressing these mutated proteins have been shown to have a reduced proliferation rate and competence, and to undergo accelerated senescence.
H1-4