The NSD1 and EZH2 Overgrowth Genes, Similarities and Differences

Authors

  • KATRINA TATTON-BROWN,

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    • Dr. Kate Tatton-Brown is a Clinical Geneticist at the Institute of Cancer Research (ICR), St. George's University of London and the Royal Marsden Hospital. She has a strong research interest and clinical experience in childhood overgrowth syndromes and has published widely on Sotos syndrome, the 15q overgrowth syndrome and, more recently, on Weaver syndrome.
  • NAZNEEN RAHMAN

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    • Nazneen Rahman is Professor of Human Genetics at the Institute of Cancer Research (ICR). She is both a clinician and world leading researcher in the field of genetic susceptibility. Her research work has been directed towards the mapping and identification of adult and pediatric cancer predisposition genes and childhood overgrowth genes. She has extensive publications and during her 13 years as a clinical academic researcher has mapped/identified 14 disease genes.

Correspondence to: Katrina Tatton-Brown, Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK. E-mail: kate.tatton-brown@icr.ac.uk

Abstract

NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone 3 (H3K36) and is primarily associated with active transcription, while EZH2 shows specificity for lysine residue 27 (H3K27) and is associated with transcriptional repression. Somatic dysregulation of NSD1 and EZH2 have been associated with tumorigenesis. NSD1, as a fusion transcript with NUP98, plays a key role in leukemogenesis, particularly childhood acute myeloid leukemia. EZH2 is a major proto-oncogene and mono- and biallelic activating and inactivating somatic mutations occur as early events in the development of tumors, particularly poor prognosis hematopoietic malignancies. Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos syndrome are loss-of-function, primarily truncating mutations or missense mutations at key residues in functional domains. EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined. Many additional questions about the molecular and clinical features of NSD1 and EZH2 remain unanswered. However, studies are underway to address these and, as more cases are ascertained and technology improves, it is hoped that these will, in time, be answered. © 2013 Wiley Periodicals, Inc.

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