Alternative titles; symbols
HGNC Approved Gene Symbol: NSD2
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38) : 4:1,871,393-1,982,192 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.3 | Rauch-Steindl syndrome | 619695 | Autosomal dominant | 3 |
The NSD2 gene encodes a SET domain-containing transcriptional regulatory protein with histone methyltransferase activity associated with actively transcribed regions of the genome during embryonic development. NSD2 is the principal enzyme that dimethylates histone H3 at lysine 36 (H3K36me2) in most cells and tissues (summary by Boczek et al., 2018 and Zanoni et al., 2021).
Wolf-Hirschhorn syndrome (WHS; 194190) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3). The shortest region of overlap of the deletions observed in WHS patients, the WHS critical region, has been confined to a region of 165 kb (Wright et al., 1997). This region was sequenced completely during the search for the Huntington disease gene (Baxendale et al., 1993). Stec et al. (1998) described a novel developmental gene, two-thirds of which maps in the distal part of the WHS critical region. They designated the gene WHSC1 (Wolf-Hirschhorn syndrome candidate-1). The WHSC1 gene was identified initially through its high similarity to the translation product of an expressed sequence tag, located in the 165-kb WHCR, with the SET domain (see 600960) of the Drosophila protein ASH1 (607999). The SET domain is found in proteins that are involved in embryonic development. The WHSC1 gene was found to be expressed ubiquitously in early development and to undergo complex alternative splicing and differential polyadenylation. It encodes a 136-kD protein containing 4 domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain also found in the Drosophila dysmorphy gene ash-encoded protein, and a PHD-type zinc finger. It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients. The nature of the protein motifs, the expression pattern, and its mapping to the critical region led Stec et al. (1998) to propose WHSC1 as a good candidate gene to be responsible for many of the phenotypic features of WHS.
Nimura et al. (2009) showed that the H3K36me3-specific histone methyltransferase Whsc1 functions in transcriptional regulation together with developmental transcription factors whose defects overlap with the human disease Wolf-Hirschhorn syndrome (WHS). Nimura et al. (2009) found that mouse Whsc1, 1 of 5 putative Set2 homologs, governed H3K36me3 along euchromatin by associating with the cell type-specific transcription factors Sall1 (602218), Sall4 (607343), and Nanog (607937) in embryonic stem cells, and Nkx2-5 (600584) in embryonic hearts, regulating the expression of their target genes. Whsc1-deficient mice showed growth retardation and various WHS-like midline defects, including congenital cardiovascular anomalies. The effects of Whsc1 haploinsufficiency were increased in Nkx2-5 heterozygous mutant hearts, indicating their functional link. Nimura et al. (2009) proposed that WHSC1 functions together with developmental transcription factors to prevent the inappropriate transcription that can lead to various pathophysiologies.
Pei et al. (2011) found that H4K20 methylation actually increases locally upon the induction of double-strand breaks and that methylation of H4K20 at double-strand breaks is mediated by the histone methyltransferase MMSET in mammals. Downregulation of MMSET significantly decreases H4K20 methylation at double-strand breaks and the subsequent accumulation of 53BP1 (605230). Furthermore, Pei et al. (2011) found that the recruitment of MMSET to double-strand breaks requires the gamma-H2AX (601772)-MDC1 (607593) pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated ser102 of MMSET. Thus, Pei et al. (2011) proposed that a pathway involving gamma-H2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around double-strand breaks, which, in turn, facilitates 53BP1 recruitment.
The WHSC1 gene contains 25 exons (Stec et al., 1998).
Stec et al. (1998) mapped the WHSC1 gene to chromosome 4p16.3 based on genomic sequence analysis.
Stec et al. (1998) noted that the t(4;14)(p16.3;q32.3) translocations described in a significant fraction of multiple myelomas (Richelda et al., 1997; Chesi et al., 1997) have breakpoints located less than 100 kb centromeric of the FGFR3 gene (134934) on 4p16.3. They found that at least 3 of the breakpoints merged the immunoglobulin heavy-chain gene (IGHG1; 147100) on chromosome 14 with the WHSC1 gene. This fusion of genes and their untimely expression in the myeloid lineage driven from the 5-prime IgH enhancer may indicate that WHSC1-encoded proteins are involved in the clinical heterogeneity of multiple myeloma.
Somatic Mutations in Cancer
Jaffe et al. (2013) profiled global histone modifications in 115 cancer cell lines from the Cancer Cell Line Encyclopedia. One signature was characterized by increased H3K36me2, exhibited by several lines harboring translocations in the NSD2 methyltransferase. An NSD2 glu1099-to-lys (E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL; 613065) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of greater than 1,000 pediatric cancer genomes identified the NSD2 E1099K alteration in 14% of t(12;21) ETV6 (600618)-RUNX1 (151385)-containing ALLs.
Rauch-Steindl Syndrome
In a 16-month-old boy with Rauch-Steindl syndrome (RAUST; 619695), Lozier et al. (2018) identified a de novo heterozygous nonsense mutation in the NSD2 gene (R1138X; 602952.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function.
In a 2-year-old girl with RAUST, Boczek et al. (2018) identified a de novo heterozygous frameshift mutation in the NSD2 gene (602952.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function.
In a 34-month-old boy (patient 2) with RAUST, Derar et al. (2019) identified a de novo heterozygous nonsense mutation in the NSD2 gene (602952.0003). Functional studies of the variant and studies of patient cells were not performed.
In a Chinese father and daughter with RAUST, Hu et al. (2020) identified a heterozygous frameshift mutation in the NSD2 gene (602952.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the father, who transmitted it to his affected daughter. The variant, which was not present in public databases, was predicted to result in nonsense-mediated mRNA decay and a loss of function, although functional studies of the variant and studies of patient cells were not performed.
In 18 patients from 16 unrelated families with RAUST, Zanoni et al. (2021) identified heterozygous variants in the NSD2 gene (see, e.g., 602952.0005-602952.0007). The variants were found by exome sequencing. Most occurred de novo, although 2 were recurrent and 2 were inherited within families. There were 5 missense variants, 3 nonsense mutations, and 7 frameshift mutations. In vitro functional expression studies showed that some, but not all, of the tested missense variants caused reduced levels of H3K36me2, impaired NSD2 methylation activity, and were unable to fully rescue physiologic levels of H3K36me2 in NSD2-depleted cells. Notably, C869Y (patient 1) and E1091K (patient 5) yielded equivocal result in functional assays, whereas S1137F (602952.0006) and K1019R (601952.0007) significantly compromised NSD2 function. The nonsense and frameshift mutations were predicted to result in a loss of function, although functional studies of these variants were not performed. Zanoni et al. (2021) concluded that the mutations result in a decrease or loss of NSD2 methyltransferase activity, which results in the developmental phenotype. While heterozygotes for missense variants were taller than those with nonsense or frameshift mutations, the overall clinical severity correlated only loosely with putative or demonstrated alterations in NSD2 enzymatic activity. Of note, several patients carried variants of uncertain significance in additional genes that could have contributed to the phenotype.
In a 16-month-old boy with Rauch-Steindl syndrome (RAUST; 619695), Lozier et al. (2018) identified a de novo heterozygous c.3412C-T transition (c.3412C-T, NM_001042424.2) in the NSD2 gene, resulting in an arg1138-to-ter (R1138X) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function.
In a 2-year-old girl with Rauch-Steindl syndrome (RAUST; 619695), Boczek et al. (2018) identified a de novo heterozygous 4-bp deletion (c.1676_1679del, NM_133330.2) in the NSD2 gene, predicted to result in a frameshift and premature termination (Arg559ThrfsTer38). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function.
In a 34-month-old boy (patient 2) with Rauch-Steindl syndrome (RAUST; 619695), Derar et al. (2019) identified a de novo heterozygous c.2803C-T transition (c.2803C-T, NM_001042424) in exon 15 of the NSD2 gene, resulting in an arg935-to-ter (R935X) substitution. Functional studies of the variant and studies of patient cells were not performed.
In a Chinese father and daughter with Rauch-Steindl syndrome (RAUST; 619695), Hu et al. (2020) identified a heterozygous 1-bp duplication (c.1577dupG, NM_001042424) in the NSD2 gene, predicted to result in a frameshift and premature termination (Asn527LysfsTer14). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the father, who transmitted it to his affected daughter. The variant, which was not present in public databases, was predicted to result in nonsense-mediated mRNA decay and a loss of function, although functional studies of the variant and studies of patient cells were not performed. The patients had mildly dysmorphic facial features and mild intellectual disability, although only the daughter had short stature, suggesting incomplete penetrance or variable expressivity.
In 2 unrelated boys (patients 11 and 15) with Rauch-Steindl syndrome (RAUST; 619695), Zanoni et al. (2021) identified a de novo heterozygous 1-bp deletion (c.4028delC, NM_133330.2) in the NSD2 gene, predicted to result in a frameshift with elongation of the protein (Pro1343GlnfsTer49). The mutation was found by exome sequencing. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In a 12-year-old Caucasian boy (patient 10) with Rauch-Steindl syndrome (RAUST; 619695), Zanoni et al. (2021) identified a de novo heterozygous c.3410C-T transition (c.3410C-T, NM_133330.2) in the NSD2 gene, resulting in a ser1137-to-phe (S1137F) substitution in the core of the methyltransferase domain. The variant was found by exome sequencing. In vitro functional expression studies showed that the variant caused reduced levels of H3K36me2, impaired NSD2 methylation activity, and was unable to fully rescue physiologic levels of H3K36me2 in NSD2-depleted cells. The findings were consistent with NSD2 deficiency. Exome sequencing showed that the patient carried variants of uncertain significance in other genes (HUWE1, 300697 and RNF38, 612488).
In a 26-year-old man (patient 12) with Rauch-Steindl syndrome (RAUST; 619695), Zanoni et al. (2021) identified a de novo heterozygous c.3056A-G transition (c.3056A-G, NM_133330.2) in the NSD2 domain, resulting in a lys1019-to-arg (K1019R) substitution in the methyltransferase domain. The variant was found by exome sequencing. In vitro functional expression studies showed that the variant caused reduced levels of H3K36me2, impaired NSD2 methylation activity, and was unable to fully rescue physiologic levels of H3K36me2 in NSD2-depleted cells. The findings were consistent with NSD2 deficiency. Exome sequencing showed that the patient carried a variant of uncertain significance in the AGO2 gene (606229).
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Hu, X., Wu, D., Li, Y., Wei, L., Li, X., Qin, M., Li, H., Li, M., Chen, S., Gong, C., Shen, Y. The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy. BMC Med. Genomics 13: 181, 2020. [PubMed: 33276791] [Full Text: https://doi.org/10.1186/s12920-020-00831-9]
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Lozier, E. R., Konovalov, F. A., Kanivets, I. V., Pyankov, D. V., Koshkin, P. A., Baleva, L. S., Sipyagina, A. E., Yakusheva, E. N., Kuchina, A. E., Korostelev, S. A. De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features. J. Hum. Genet. 63: 919-922, 2018. [PubMed: 29760529] [Full Text: https://doi.org/10.1038/s10038-018-0464-5]
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Pei, H., Zhang, L., Luo, K., Qin, Y., Chesi, M., Fei, F., Bergsagel, P. L., Wang, L., You, Z., Lou, Z. MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 470: 124-128, 2011. [PubMed: 21293379] [Full Text: https://doi.org/10.1038/nature09658]
Richelda, R., Ronchetti, D., Baldini, L., Cro, L., Viggiano, L., Marzella, R., Rocchi, M., Otsuki, T., Lombardi, L., Maiolo, A. T., Neri, A. A novel chromosomal translocation t(4;14)(p16.3;q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. Blood 90: 4062-4070, 1997. [PubMed: 9354676]
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Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., and 22 others. Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype. Genet. Med. 23: 1474-1483, 2021. [PubMed: 33941880] [Full Text: https://doi.org/10.1038/s41436-021-01158-1]