Abstract
The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.
Highlights
Histones are DNA-binding proteins constituting the building blocks of chromatin, i.e. the nucleosomes, and play an important role in the epigenetic regulation of chromatin compaction, gene transcription and other processes such as DNA damage repair
Histone H3 consists of canonical isoforms H3.1 and H3.2, which can be replaced by multiple H3 variants such as H3.3 encoded by two genes H3-3A and H3-3B that are expressed in both embryonic and differentiated cells[1,2,3]
Molecular findings All but one individuals were found to have de novo missense variants in evolutionarily highly conserved amino acids encoded by either H3-3A or H3-3B (Fig. 1), while the remaining individual (Individual 10) was found to have a de novo stop loss variant in H3-3B, which is predicted to result in incorporation of additional nine amino acids to the wild type protein (Table 1)
Summary
Histones are DNA-binding proteins constituting the building blocks of chromatin, i.e. the nucleosomes, and play an important role in the epigenetic regulation of chromatin compaction, gene transcription and other processes such as DNA damage repair. The role of chromatin dysregulation in neurodevelopmental multisystemic disorders have been described by several studies[4,5,6]. Mutations in H3.3 genes have been implicated in human malignancies via promoting tumorigenesis by perturbing H3.3 chromatin-related epigenetic functions[7]. De novo missense variants in H3-3A and H3-3B have been reported to be associated with neurodevelopmental delay and neurologic abnormalities in a cohort of 46 individuals[8,9]. We report de novo missense and stop-loss variants in H3-3A (n = 6) and H3-3B (n = 6) in 12 individuals with neurodevelopmental disorders and multiple system abnormalities
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