Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for histone H3 at lysine 27 (H3K27) trimethylation. A de novo missense mutation found in a patient affected by overgrowth Weaver syndrome [c.1876G.A (p.Val626Met)] is associated with decreased histone methyltransferase activity in growth plate chondrocytes. This Ezh2(V626M) mouse strain carries a corresponding CRISPR/Cas9-generated V626M (valine to methionine) point mutation of mouse Ezh2 gene. Homozygotes show perinatal lethality, whereas heterozygotes are viable, fertile, and show mild overgrowth. At 8 weeks, overall body weight is increased in heterozygous Weaver mice, more prominently in females. Compared with human patients with Weaver syndrome, the overgrowth found in mice appears relatively mild. Tibia lengths are not different between wildtype and heterozygous mice, whereas the weights of heart, kidney, and spleen are increased in heterozygotes. The increase in the weight of the spleen raises the possibility of increased lymphocyte proliferation, which might be related to a possible increased risk of leukemia and lymphoma in Weaver syndrome suggested by some reports. Immunohistochemistry of E14.5 embryos demonstrates that normal levels of EXH2 protein are produced by heterozygous and homozygous Exh2(V626M) mice, but both homozygous and heterozygous embryos show decreased H3K27 histone methylation.

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Ezh2(V626M) are CRISPR/Cas9-derived mice carrying the V662M mutation associated with Weaver syndrome. Heterozygotes recapitulate a mild Weaver overgrowth phenotype and demonstrate decreased H3K27 methylation.

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