The EZH2 gene encodes a histone methyltransferase. This enzyme is a member of the Polycomb-group (PcG) family that forms multimeric protein complexes, which play a role in maintaining the transcriptional repressive state of certain genes for successive cell generations. The encoded protein also interacts with several proteins including the VAV1 oncoprotein. It is also involved in the di- and trimethylation of Lys-27 of histone H3 on PER1/2 promoters which is essential for the CRY1/2 proteins to inhibit transcription. The dysregulation of this methylation is associated with the development of various types of cancers including: prostate cancer, lymphomas and leukemias. In addition, defects in this enzyme are associated with Weaver syndrome, characterized by accelerated growth and osseous maturation, hoarse and low-pitched cry, unusual craniofacial appearance, and hypertonia with camptodactyly.
The EZH2 gene consists of 19 coding exons spanning approximately 77 kb on the long arm of chromosome 7. This gene has multiple alternatively spliced transcript variants encoding different isoforms. It encodes a protein of 746 amino acids with a molecular mass of about 85 kDa. At least 30 different mutations in the EZH2 gene have been identified in patients with Weaver syndrome. Mutations in this gene have also been associated with various types of cancers such as: prostate, breast, lymphomas and leukemias.
Al-Salem et al., (2013) described a 15-month-old boy with Weaver Syndrome who presented with remarkably accelerated growth pattern; his growth parameters were: weight 18.2 kg, length 89 cm, and OFC 49 cm. He had a flat occiput, downslanting palpebral fissures, round face, retrognathia, and hypertelorism with mild degree of exophthalmos. His physical examination showed umbilical hernia and discrepancy in the size of the lower extremities with the left side being smaller. The left side of his body also showed exaggerated reflexes, increased tone, and reduction of power. A de novo c.2233G>A missense mutation in exon 20 of the EZH2 gene was identified in the affected patient, resulting in a Glu745Lys amino acid substitution. This mutation was not found in 200 Saudi Exomes and the Exome Variants Server (ESV) and this de novo mutation is likely to be disease causing.
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