6kqp

Structural highlights

Disease

[NSD1_HUMAN] Sotos syndrome;Beckwith-Wiedemann syndrome due to NSD1 mutation;5q35 microduplication syndrome;Weaver syndrome. Sotos syndrome 1 (SOTOS1) [MIM:117550]: A childhood overgrowth syndrome characterized by pre- and postnatal overgrowth, developmental delay, mental retardation, advanced bone age, and abnormal craniofacial morphology including macrodolichocephaly with frontal bossing, frontoparietal sparseness of hair, apparent hypertelorism, downslanting palpebral fissures, and facial flushing. Common oral findings include: premature eruption of teeth; high, arched palate; pointed chin and, more rarely, prognathism. Note=The disease is caused by mutations affecting the gene represented in this entry.^{[1] [2] [3] [4] [5]} Weaver syndrome 1 (WVS1) [MIM:277590]: A syndrome of accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly. Distinguishing features of Weaver syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails. In addition, carpal bone development is advanced over the rest of the hand. Note=The disease is caused by mutations affecting the gene represented in this entry.^{[6] [7]} Beckwith-Wiedemann syndrome (BWS) [MIM:130650]: A disorder characterized by anterior abdominal wall defects including exomphalos (omphalocele), pre- and postnatal overgrowth, and macroglossia. Additional less frequent complications include specific developmental defects and a predisposition to embryonal tumors. Note=The disease is caused by mutations affecting the gene represented in this entry.^[8] Note=A chromosomal aberration involving NSD1 is found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NUP98. Note=A chromosomal aberration involving NSD1 is found in an adult form of myelodysplastic syndrome (MDS). Insertion of NUP98 into NSD1 generates a NUP98-NSD1 fusion product.

Function

[NSD1_HUMAN] Histone methyltransferase. Preferentially methylates 'Lys-36' of histone H3 and 'Lys-20' of histone H4 (in vitro). Transcriptional intermediary factor capable of both negatively or positively influencing transcription, depending on the cellular context.^[9]

References

1. ↑ Qiao Q, Li Y, Chen Z, Wang M, Reinberg D, Xu RM. The Structure of NSD1 Reveals an Autoregulatory Mechanism Underlying Histone H3K36 Methylation. J Biol Chem. 2011 Mar 11;286(10):8361-8. Epub 2010 Dec 31. PMID:21196496 doi:10.1074/jbc.M110.204115
2. ↑ Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, Ohashi H, Naritomi K, Tsukahara M, Makita Y, Sugimoto T, Sonoda T, Hasegawa T, Chinen Y, Tomita Ha HA, Kinoshita A, Mizuguchi T, Yoshiura Ki K, Ohta T, Kishino T, Fukushima Y, Niikawa N, Matsumoto N. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet. 2002 Apr;30(4):365-6. Epub 2002 Mar 18. PMID:11896389 doi:10.1038/ng863
3. ↑ Baujat G, Rio M, Rossignol S, Sanlaville D, Lyonnet S, Le Merrer M, Munnich A, Gicquel C, Cormier-Daire V, Colleaux L. Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome. Am J Hum Genet. 2004 Apr;74(4):715-20. Epub 2004 Mar 1. PMID:14997421 doi:10.1086/383093
4. ↑ Douglas J, Hanks S, Temple IK, Davies S, Murray A, Upadhyaya M, Tomkins S, Hughes HE, Cole TR, Rahman N. NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. Am J Hum Genet. 2003 Jan;72(1):132-43. Epub 2002 Dec 2. PMID:12464997
5. ↑ Rio M, Clech L, Amiel J, Faivre L, Lyonnet S, Le Merrer M, Odent S, Lacombe D, Edery P, Brauner R, Raoul O, Gosset P, Prieur M, Vekemans M, Munnich A, Colleaux L, Cormier-Daire V. Spectrum of NSD1 mutations in Sotos and Weaver syndromes. J Med Genet. 2003 Jun;40(6):436-40. PMID:12807965
6. ↑ Douglas J, Hanks S, Temple IK, Davies S, Murray A, Upadhyaya M, Tomkins S, Hughes HE, Cole TR, Rahman N. NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. Am J Hum Genet. 2003 Jan;72(1):132-43. Epub 2002 Dec 2. PMID:12464997
7. ↑ Rio M, Clech L, Amiel J, Faivre L, Lyonnet S, Le Merrer M, Odent S, Lacombe D, Edery P, Brauner R, Raoul O, Gosset P, Prieur M, Vekemans M, Munnich A, Colleaux L, Cormier-Daire V. Spectrum of NSD1 mutations in Sotos and Weaver syndromes. J Med Genet. 2003 Jun;40(6):436-40. PMID:12807965
8. ↑ Baujat G, Rio M, Rossignol S, Sanlaville D, Lyonnet S, Le Merrer M, Munnich A, Gicquel C, Cormier-Daire V, Colleaux L. Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome. Am J Hum Genet. 2004 Apr;74(4):715-20. Epub 2004 Mar 1. PMID:14997421 doi:10.1086/383093
9. ↑ Qiao Q, Li Y, Chen Z, Wang M, Reinberg D, Xu RM. The Structure of NSD1 Reveals an Autoregulatory Mechanism Underlying Histone H3K36 Methylation. J Biol Chem. 2011 Mar 11;286(10):8361-8. Epub 2010 Dec 31. PMID:21196496 doi:10.1074/jbc.M110.204115
10. ↑ Huang H, Howard CA, Zari S, Cho HJ, Shukla S, Li H, Ndoj J, Gonzalez-Alonso P, Nikolaidis C, Abbott J, Rogawski DS, Potopnyk MA, Kempinska K, Miao H, Purohit T, Henderson A, Mapp A, Sulis ML, Ferrando A, Grembecka J, Cierpicki T. Covalent inhibition of NSD1 histone methyltransferase. Nat Chem Biol. 2020 Aug 31. pii: 10.1038/s41589-020-0626-6. doi:, 10.1038/s41589-020-0626-6. PMID:32868895 doi:http://dx.doi.org/10.1038/s41589-020-0626-6