EZH1(Enhancer of Zeste, homolog 1), a Polycomb Repressive Complex-2 (PRC2) component, is involved in a myriad of cellular processes through modifying histone 3 lysine27 (H3K27) residues.EZH1represses transcription of downstream target genes through H3K27 trimethylation (H3K27me3). Genetic mutations in histone modifiers have been associated with developmental disorders, whileEZH1has not yet been linked to any human disease. However, the paralogEZH2is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have ade novovariant inEZH1, p.Ala678Gly, through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and was the best candidate variant found in the exome. HumanEZH1/2are homologous to flyEnhancer of zeste E(z), an essential gene in flies, and the residue (A678 in humans, A691 inDrosophila) is conserved. To further study this variant, we obtainedDrosophilanull alleles and generated transgenic flies expressing wild-type(E(z)WT)and the variant(E(z)A691G). TheE(z)A691Gvariant led to hyper H3K27me3 while theE(z)WTdid not, suggesting this is as a gain-of-function allele. When expressed under the tubulin promotorin vivothe variant rescued null-lethality similar to wild-type but theE(z)A691Gflies exhibit bang sensitivity and shortened lifespan. In conclusion, here we present a novelEZH1 de novovariant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact inDrosophila. Biochemically this allele leads to increased H3K27me3 suggesting gain-of-function, but when expressed in adult flies theE(z)A691Ghas some characteristics of partial loss-of-function which may suggest it is a more complex allelein vivo.
EZH1, a Polycomb Repressive Complex-2 (PRC2) component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo missense variant in EZH1 through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and an analogous somatic or germline mutation in EZH2 has been reported in patients with B-cell lymphoma or Weaver syndrome, respectively. Human EZH1/2 are homologous to fly Enhancer of zeste, E(z), an essential gene in Drosophila, and the affected residue (p.A678 in humans, p.A691 in flies) is conserved. To further study this variant, we obtained null alleles and generated transgenic flies expressing wildtype [E(z)WT] and the variant [E(z)A691G]. When expressed ubiquitously the variant rescues null-lethality similar to the wildtype. Overexpression of E(z)WT induces homeotic patterning defects but notably the E(z)A691G variant leads to dramatically stronger morphological phenotypes. We also note a dramatic loss of H3K27me2 and a corresponding increase in H3K27me3 in flies expressing E(z)A691G, suggesting this acts as a gain-of-function allele. In conclusion, here we present a novel EZH1 de novo variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila.
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