Several forms of pediatric glioma show a high frequency of heterozygous mutation in one of the human histone H3.3 genes, H3-3A (also known as H3F3A). In particular, the amino acid substitution K28M (K27M) is frequently observed. (Alternate designation K27M: the histone 3 polypeptide undergoes co-translational N-terminal methionine cleavage, thus the functional protein is one amino acid shorter.) There are two genes that encode the H3.3 histone variant in both human and in Drosophila; all have identical protein sequences 136aa in length.
A tagged human Hsap\H3-3A UAS-transgene carrying the K28M (K27M) variant has been introduced into flies. Depending upon the GAL4 driver used, developmental abnormalities of various types are observed; changes in chromatin signatures have been characterized.
The K28M (K27M) variant has also been introduced into the Drosophila His3.3A gene. Using assays in the developing eye, it has been shown that deleterious effects are observed only when the variant is expressed in proliferating cells.
See the 'Disease-Implicated Variants' table below.
[updated Jun. 2022 by FlyBase; FBrf0222196]
In a sample of 48 cases of pediatric glioblastoma, recurrent mutations in H3F3A, which encodes the replication-independent histone-3 variant H3.3, were observed in 31% of tumors; observed mutations resulted in amino acid substitutions at 2 critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory posttranslational modifications (Schwartzentruber et al., 2012; pubmed:22286061). Over 70% of diffuse intrinsic pediatric gliomas, exhibit heterozygous mutations that create a K27M substitution in H3.3 (Funato et al., 2014; pubmed:25525250). [from MIM:601128; 2016.09.30]
Glioblastoma multiforme and other malignant gliomas are characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy (Ramirez et al., 2013; pubmed:24287492).
H3-3A encodes a variant histone H3 (H3.3)which replaces conventional H3 in a wide range of nucleosomes in active genes and may represent an epigenetic imprint of transcriptionally active chromatin. Constitutes the predominant form of histone H3 in non-dividing cells and is incorporated into chromatin independently of DNA synthesis. [from Gene Cards, H3-3A; 2019.11.05]
Designation of affected lysine (K27 vs. K28): Alternative numeration of histone amino acids is based on initial papers that disregarded the first methionine, as it is cleaved in an early posttranslational state and was initially not detected (Leske et al., 2018; pubmed:29766298). Using current conventions for designation of mutational lesions, K28 is preferred.
Many to many (2 human to 2 Drosophila). There are two genes that encode the H3.3 histone variant in each species: H3F3A and H3F3B in human; His3.3A and His3.3B in Drosophila. All have identical protein sequences 136aa in length.
