Abstract Link: Nat Genet. 2019 Jan;51(1):96105.
In brief: Gain-of-function mutations altering DNMT3A are identified as a new cause of microcephalic dwarfism. Modelling of the disease in mice show that the mutations abrogate DNMT3A binding to H3K36me2 and H3K36me3 and lead to aberrant DNA methylation of Polycomb-marked regions and therefore repression of growth genes.
Comment: DNMT3A codes for a de novo DNA methyltransferase, which is particularly important for establishing DNA methylation patterns during early development. Loss-of-function mutations in DNMT3A have recently been shown to cause an overgrowth syndrome with macrocephaly and intellectual disability (Tatton-Brown-Rahman syndrome) (1). Interestingly, genome/exome sequencing of a large number of individuals with presumed monogenic tall stature identified mutations in several genes involved in creating and maintaining DNA and histone modifications, e.g. NSD1, EZH2, and DNMT3A, indicating that mutations in epigenetic modifiers are a relatively frequent cause of syndromic tall stature (2). The mechanism by which these mutations cause overgrowth is not completely clear, but likely include derepression of growth-promoting genes expressed in the growth plate (3). Interestingly, in the current study, the authors identified gain-of-function mutations in DNMT3A as a new cause of severe microcephalic dwarfism.
Furthermore, studies of knock-in mice with a similar (orthologous) mutation replicated the phenotype and shed light on the pathogenic mechanism. The mutations abrogated DNMT3A binding to Histone 3 molecules that are di- or trimethylated at Lysine 36 (H3K36me2 and H3K36me3) and also led to aberrant DNA methylation of Polycomb-marked regions and thereby repressing growth-promoting genes and/or upregulating growth-inhibiting genes.
References: 1. Tatton-Brown, K. et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat. Genet. 46, 385388 (2014).
2. Tatton-Brown, K. et al. Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. American Journal of Human Genetics 100, 725736, doi:10.1016/j.ajhg.2017.03.010 (2017).
3. Lui, J. C. et al. EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy. Nat Commun 7, 13685, doi:10.1038/ncomms13685 (2016).