The NSD1 and EZH2 overgrowth genes, similarities and differences

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.

Figure 1. Domain structure of NSD1 and EZH2 SET domain-containing histone methyltransferases

a) NSD1 is a 2696 amino acid protein with ten conserved domains in addition to the SET and preceding SAC domains whilst EZH2 is a 746 amino acid protein with two SANT domains in addition to the SET and SAC. b) NSD1 is a histone methyltransferase which preferentially mono or di- methylates lysine residue 36 of histone 3 whereas EZH2 can catalyse the transfer of up to three methyl groups to lysine residue 27 of histone 3. NID, Nuclear interacting domain; PWWP, Proline, tryptophan, tryptophan, proline; PHD, plant homeodomain; SANT, Swi3, Ada2, N-cor TFIIIB.

Figure 2. Facial appearance of children and adults with a)NSD1 mutations and b) EZH2 mutations