“…14 Although its precise functions remain largely unknown, NSD1 is believed to have a role in transcriptional regulation through methylation of histone lysine residues, the differential binding of its two nuclear receptor-interacting domains and chromatin-chromatin interactions. [15][16][17] The portion of the human genome surrounding NSD1, often referred to as the Sotos critical region, encompasses 1.1 Mb of DNA, contains approximately 21 genes ( Figure 1a) and is flanked by two well-characterized low-copy repeats ( Figure 1c): a proximal 390 kb repeat (Sos-PREP) and a distal 429 kb repeat (Sos-DREP). 18 A common microdeletion 19 mediated by directly oriented subunits within Sos-PREP and Sos-DREP 18 is the most common mutational mechanism in the Japanese population, whereas intragenic mutations are responsible for at least 80% of the reported cases in European and North American patients.…”
Genomic rearrangements are an increasingly recognized mechanism of human phenotypic variation and susceptibility to disease. Sotos syndrome is characterized by overgrowth, macrocephaly, developmental delay and advanced osseous maturation. Haploinsufficiency of NSD1, caused by inactivating point mutations or deletion copy number variants, is the only known cause of Sotos syndrome. A recurrent 2 Mb deletion has been described with variable frequency in different populations. In this study, we report two individuals of different ethnic and geographical backgrounds, with duplications reciprocal to the common Sotos syndrome deletion. Our findings provide evidence for the existence of a novel syndrome of short stature, microcephaly, delayed bone development, speech delay and mild or absent facial dysmorphism. The phenotype is remarkably opposite to that of Sotos syndrome, suggesting a role for NSD1 in the regulation of somatic growth in humans.
“…14 Although its precise functions remain largely unknown, NSD1 is believed to have a role in transcriptional regulation through methylation of histone lysine residues, the differential binding of its two nuclear receptor-interacting domains and chromatin-chromatin interactions. [15][16][17] The portion of the human genome surrounding NSD1, often referred to as the Sotos critical region, encompasses 1.1 Mb of DNA, contains approximately 21 genes ( Figure 1a) and is flanked by two well-characterized low-copy repeats ( Figure 1c): a proximal 390 kb repeat (Sos-PREP) and a distal 429 kb repeat (Sos-DREP). 18 A common microdeletion 19 mediated by directly oriented subunits within Sos-PREP and Sos-DREP 18 is the most common mutational mechanism in the Japanese population, whereas intragenic mutations are responsible for at least 80% of the reported cases in European and North American patients.…”
Genomic rearrangements are an increasingly recognized mechanism of human phenotypic variation and susceptibility to disease. Sotos syndrome is characterized by overgrowth, macrocephaly, developmental delay and advanced osseous maturation. Haploinsufficiency of NSD1, caused by inactivating point mutations or deletion copy number variants, is the only known cause of Sotos syndrome. A recurrent 2 Mb deletion has been described with variable frequency in different populations. In this study, we report two individuals of different ethnic and geographical backgrounds, with duplications reciprocal to the common Sotos syndrome deletion. Our findings provide evidence for the existence of a novel syndrome of short stature, microcephaly, delayed bone development, speech delay and mild or absent facial dysmorphism. The phenotype is remarkably opposite to that of Sotos syndrome, suggesting a role for NSD1 in the regulation of somatic growth in humans.
“…NSD1 contains a Cys-rich region, which is composed of different arrangements of three conserved motifs, corresponding to a protein domain that has been called SAC for SET-associated Cys-rich domain. 12 The SAC domain may have a function in chromosome binding. In addition to the SET and SAC domains, NSD1 contains six other domains including two proline -tryptophan -tryptophan -proline (PWWP) domains and five plant homeodomain protein (PHD) domains.…”
mentioning
confidence: 99%
“…It has been suggested that the PHD finger domains involve chromatinmediated transcriptional regulation. 12 The PWWP domain is thought to be involved in protein -protein interactions. 13 Adjacent to the C-terminus of the PHD-V domain is another region rich in cysteines and histidines, possibly corresponding to a zinc-finger-like motif.…”
mentioning
confidence: 99%
“…The function of NSD1 remains largely unknown; however, the presence of activating as well as silencing domains and its property to bind liganded as well as unliganded NRs suggest that NSD1 could be a versatile NR intermediary factor controlling transcription either negatively or positively. 12 The observation that haploinsufficiency of NSD1 induces overgrowth prompted Kurotaki et al 5 to suggest that NSD1 acts as a corepressor of genes that promote growth.…”
“…NSD1 also includes two nuclear receptor interaction domains NID ÀL and NID þ L that are found in corepressors and coactivators, respectively. 7 The SET, PHD and one of the PWWP domains are clustered in the 3 0 end of the gene between exons 11 -23 and missense base substitutions within these domains are sufficient to cause Sotos syndrome, whereas missense base substitutions elsewhere in the gene do not appear to be pathogenic. 2 -5 NSD1 is also known to be fused with NUP98 in the t(5;11)(q35;p15.5) translocation found in childhood acute myeloid leukaemia.…”
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.