This page was published for Genetics 564 at the University of Wisconsin-Madison
Overview of the NSD1 gene
The nuclear receptor SET domain-containing protein 1 (NSD1) is found on the long arm of chromosome 5 at location 35 from base pair 176,560,025 to base pair 176,727,213. The gene gives rise to a 12998 base pair mRNA consisting of 23 exons which then encodes for a 2696 amino acid sequence [1][2][3].
NSD1 acts as a histone methyltransferase to help manage gene regulation at locations necessary for cell differentiation. If the gene is mutated, however, the ability to both bind and methylate the histones is significantly reduced. The specific sites of methylation are H3K36 (the lysine residue on the H3 subunit of the histone) and H4K44. Until recently, it was thought that NSD1 methylated H3K36 and H4K20, but after further analysis, a paper published in February of 2014 released information suggesting that NSD1 does not, in fact, methylate H4K20 but instead acts upon H4K44 [4]. Prior to this paper, the only known site on H4 that could be methylated was K20, however, further investigation, K44 was identified as another site of potential modification, and previous studies concluding that the K20 site was methylated were observing results from a cross-reactivity from the K44 site [4]. It has also been discovered that there are 25 non-histone targets of NSD1. However out of these 25, only two were able to be methylated. These two proteins do not have any known inherent effects in producing the Sotos phenotype [4].
This gene encodes for a number of domains on the protein, as can be seen further analyzed on the Domains and Motifs page. As mutations in each individual domain results in the same general phenotype as deletions that eliminate the entire NSD1 gene, it can be determined that all domains are of the utmost importance [5]. Mutations that give rise to this Sotos phenotype have a variety of manifestations. Two classes of mutations arose resulting in gene truncation: microdeletions (more commonly represented in the Japanese population) and intragenic mutations (insertions, deletions, frameshift, nonsense, or splice-site mutations). There is evidence of familial transmission, however enough non-familial cases arise to denote that Sotos mutations are not predominantly due to inheritance [6].
This gene encodes for a number of domains on the protein, as can be seen further analyzed on the Domains and Motifs page. As mutations in each individual domain results in the same general phenotype as deletions that eliminate the entire NSD1 gene, it can be determined that all domains are of the utmost importance [5]. Mutations that give rise to this Sotos phenotype have a variety of manifestations. Two classes of mutations arose resulting in gene truncation: microdeletions (more commonly represented in the Japanese population) and intragenic mutations (insertions, deletions, frameshift, nonsense, or splice-site mutations). There is evidence of familial transmission, however enough non-familial cases arise to denote that Sotos mutations are not predominantly due to inheritance [6].
Nuclear receptor SET domain-containing protein 1 (NSD1) specifications:
Gene Accession Number: NM_022455.4
GI Number: 182507166
FASTA
Gene Accession Number: NM_022455.4
GI Number: 182507166
FASTA
References:
[1] Genetics Home Reference. (2014). NSD1. Retrieved: February 4, 2014, from http://ghr.nlm.nih.gov/gene/NSD1
[2] NCBI BLAST results: http://www.ncbi.nlm.nih.gov/nuccore/182507166?report=genbank&to=12998
[3] GeneDx. (2013). NSD1 gene analysis in Sotos syndrome. Retrieved February 15, 2014, from https://www.genedx.com/wp-content/uploads/crm_docs/info_sheet_nsd.pdf
[4] Kudithipudi, S., Lungu, C., Rathert, P., Happel, N., & Jeltsch, A. (2014). Substrate specificity analysis and novel substrates of the protein lysine methyltransferase NSD1. Chem Biol, 21(2), 226-237. doi: 10.1016/j.chembiol.2013.10.016
[5] Novara, F., Stanzial, F., Rossi, E., Benedicenti, F., Inzana, F., Di Gregorio, E., . . . Ciccone, R. (2014). Defining the phenotype associated with microduplication reciprocal to Sotos syndrome microdeletion. Am J Med Genet A. doi: 10.1002/ajmg.a.36591
[6] Tatton-Brown, K., Douglas, J., et.al. (2005). Genotype-Phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. The American Journal of Human Genetics, 77(2), 193-204. doi: http://dx.doi.org/10.1086/432082
[1] Genetics Home Reference. (2014). NSD1. Retrieved: February 4, 2014, from http://ghr.nlm.nih.gov/gene/NSD1
[2] NCBI BLAST results: http://www.ncbi.nlm.nih.gov/nuccore/182507166?report=genbank&to=12998
[3] GeneDx. (2013). NSD1 gene analysis in Sotos syndrome. Retrieved February 15, 2014, from https://www.genedx.com/wp-content/uploads/crm_docs/info_sheet_nsd.pdf
[4] Kudithipudi, S., Lungu, C., Rathert, P., Happel, N., & Jeltsch, A. (2014). Substrate specificity analysis and novel substrates of the protein lysine methyltransferase NSD1. Chem Biol, 21(2), 226-237. doi: 10.1016/j.chembiol.2013.10.016
[5] Novara, F., Stanzial, F., Rossi, E., Benedicenti, F., Inzana, F., Di Gregorio, E., . . . Ciccone, R. (2014). Defining the phenotype associated with microduplication reciprocal to Sotos syndrome microdeletion. Am J Med Genet A. doi: 10.1002/ajmg.a.36591
[6] Tatton-Brown, K., Douglas, J., et.al. (2005). Genotype-Phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. The American Journal of Human Genetics, 77(2), 193-204. doi: http://dx.doi.org/10.1086/432082