Evaluation of NSD2 and NSD3 in overgrowth syndromes

Abstract

Sotos syndrome is an overgrowth condition predominantly caused by truncating mutations, missense mutations restricted to functional domains, or deletions of NSD1. NSD1 is a member of a protein family that includes NSD2 and NSD3, both of which show 70-75% sequence identity with NSD1. This strong sequence similarity suggests that abrogation of NSD2 or NSD3 function may cause non-NSD1 Sotos cases or other overgrowth phenotypes. To evaluate this hypothesis, we mutationally screened NSD2 and NSD3 in 78 overgrowth syndrome cases in which NSD1 mutations and deletions had been excluded. Additionally, we used microsatellite markers within the vicinity of the genes to look for whole gene deletions. No truncating mutations or gene deletions were identified in either gene. We identified two conservative missense NSD2 alterations in two non-Sotos overgrowth cases but neither was within a functional domain. We identified three synonymous and two intronic variants in NSD2 and two synonymous base substitutions in NSD3. Our results suggest that despite strong sequence similarity between NSD1, NSD2 and NSD3, the latter genes are unlikely to be making a substantial contribution to overgrowth phenotypes and thus may operate in distinct functional pathways from NSD1.

Epigenetic regulation of normal and malignant hematopoiesis

“…NSD1, which methylates H3K36 and H4K20 residues, is implicated in AML as a result of the t(5;11) translocation that fuses NSD1 to NUP98, a subunit of the nuclear pore complex that is frequently rearranged in leukemia (Jaju et al, 2001). In humans, mutation of NSD1 is associated with familial gigantism (van Haelst et al, 2005), as well as with Sotos syndrome, which is characterized by fetal overgrowth, malformations and increased risk of leukemia, suggesting that NSD1 might function as a tumor suppressor (Kurotaki et al, 2002;Douglas et al, 2005). MMSET (NSD2) was identified at the breakpoint of the t(4;14) translocation present in B15% of multiple myelomas, which results in the overexpression of both FGFR3 and MMSET (Chesi et al, 1998;Stec et al, 1998).…”

The Brd4 Extraterminal Domain Confers Transcription Activation Independent of pTEFb by Recruiting Multiple Proteins, Including NSD3

“…The NSD family of proteins is essential in development and is mutated in human acute myeloid leukemia, Sotos syndrome, multiple myeloma, and lung cancer (14,26,39,47,49). The SET domain of NSD proteins is homologous to the Saccharomyces cerevisiae histone-3 lysine-36 (H3K36)-specific methyltransferase SET2 and is specific for H3K36 dimethylation (H3K36me2) (30).…”

The Methyltransferase NSD3 Has Chromatin-binding Motifs, PHD5-C5HCH, That Are Distinct from Other NSD (Nuclear Receptor SET Domain) Family Members in Their Histone H3 Recognition

“…For example, NSD1 defective mice exhibit embryonic lethality, but mice defective in NSD2 die shortly after birth and exhibit a spectrum of defects that are consistent with Wolf-Hirschhorn syndrome (13,14). It has been suspected that functional diversity of the three NSD proteins might originate from different substrate specificities of their SET domains (15). Although there have been several conflicting reports on the catalytic activities of NSD proteins, it has become clear that all three members are highly specific H3K36 mono-and dimethylases when nucleosomes are used as their substrates (16 -18).…”

“…In this study, we demonstrate that the PHD5-C5HCH module of NSD3 (PHD5-C5HCH NSD3 ) recognizes the H3 N-terminal peptide containing unmodified K4 and trimethylated K9. We have solved high resolution crystal structures of PHD5-C5HCH NSD3 in its free state and in complex with unmodified H3 residues 1-7 (H3 1-7 ), residues 1-15 (H3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] ), and residues 1-15 with trimethylation on lysine 9 (H3 1-15 K9me3), respectively. These structures reveal an integrated tandem PHD-PHD-like fold with H3 peptide bound only on the surface of PHD5 and provide the structural basis for peptide recognition by PHD5 of NSD3.…”