This report describes NSD1 duplication syndrome; a key aspect of this syndrome is reduced growth phenotypes. In contrast, deletions or severe loss-of-function mutations of NSD1 are implicated in an overgrowth syndrome (Soros syndrome 1; MIM:117550). NSD1 encodes a histone methyltransferase that dimethylates Lys36 of histone H3; it acts as a transcriptional regulator. There is a single orthologous gene in Drosophila, NSD, for which multiple genetic reagents have been generated, including RNAi-targeting constructs, overexpression constructs, and a targeted CRISPR knockout construct. Dmel\NSD is also orthologous to human NSD2 and NSD3.
The human NSD1 gene has not been introduced into flies.
Ubiquitous overexpression of Dmel\NSD during early development (using maternal drivers) results in developmental delay and reduced body size at the larval stage, resulting in pupal lethality. NSD overexpression in this system has been shown to enhance the transcription of pro-apoptotic genes and to activate caspases. In the brain, wild-type expression of NSD is restricted to a subset of glial cells. A small number of physical interactions have been described for Dmel\NSD; see below and in the NSD gene report.
[updated Jan. 2021 by FlyBase; FBrf0222196]
Microduplications of the Sotos syndrome region containing NSD1 on 5q35 have been proposed to cause a syndrome of microcephaly, short stature and developmental delay (Rosenfeld et al., 2013; pubmed:23599694).
Characterization of overlapping duplications suggests that whole-gene duplication of NSD1 in and of itself may be sufficient to cause the observed abnormal growth parameters (Rosenfeld et al., 2013; pubmed:23599694).
NSD1 encodes a histone methyltransferase that dimethylates Lys-36 of histone H3 (H3K36me2) and acts as a transcriptional intermediary factor capable of both negatively or positively influencing transcription, depending on the cellular context. [Gene Cards, NSD1; 2021.01.06]
Many to one: 3 human genes to 1 Drosophila gene.
Moderate- to high-scoring ortholog of human NSD3, NSD2, and NSD1 (1 Drosophila to 3 human). Dmel\NSD shares 25-27% identity and 40-42% similarity with the human genes. NSD1 encodes a significantly larger protein, with additional amino-terminal residues.
