Disease relevance of NSD1

• A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia [1].
• Cryptic insertion producing two NUP98/NSD1 chimeric transcripts in adult refractory anemia with an excess of blasts [2].
• This is the first report of an adult with myelodysplastic syndrome (MDS) harboring an NUP98/NSD1 fusion resulting from insertion of 5'-NUP98 into the NSD1/5q35 locus [2].
• Familial gigantism caused by an NSD1 mutation [3].
• Surprisingly, in Group I, two SS patients had 11p15 abnormalities and two patients with Beckwith-Wiedemann syndrome had NSD1 aberrations [4].

Psychiatry related information on NSD1

• Interestingly, mental retardation was consistently more severe in patients with NSD1 deletions [5].
• A pre-operative speech discrimination score of 80% was obtained at 68.9 dB for SDE and at 76.0 dB for STO [6].

High impact information on NSD1

• We isolated NSD1 from the 5q35 breakpoint in an individual with Sotos syndrome harboring a chromosomal translocation [7].
• Homozygous mutant NSD1 embryos, which initiate mesoderm formation, display a high incidence of apoptosis and fail to complete gastrulation, indicating that NSD1 is a developmental regulatory protein that exerts function(s) essential for early post-implantation development [8].
• We reviewed the clinical phenotypes of 239 NSD1-positive individuals [9].
• The reasons for the low vertical transmission rate are unclear, although familial cases were more likely than nonfamilial cases (P = .005) to carry missense mutations, suggesting that the underlying NSD1 mutational mechanism in Sotos syndrome may influence reproductive fitness [9].
• These results suggest that the two disorders may have more similarities than previously thought and that NSD1 could be involved in imprinting of the chromosome 11p15 region [10].

Biological context of NSD1

• Thus, Nizp1 contains a novel type of zinc finger motif that functions as a docking site for NSD1 and is more than just a degenerate evolutionary remnant of a C2H2 motif [11].
• It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1 [12].
• Truncating NSD1 mutations occurred throughout the gene, but pathogenic missense mutations occurred only in functional domains (P < 2 x 10(-16)) [9].
• Breakpoint mapping by FISH and reverse transcriptase polymerase chain reaction (RT-PCR) analysis confirmed that this was the same t(5;11) as previously identified in 3 children with AML, associated with del(5q) and resulting in the NUP98-NSD1 gene fusion [13].
• NSD1 consists of at least 23 exons [14].

Anatomical context of NSD1

• NSD1 is expressed in the fetal/adult brain, kidney, skeletal muscle, spleen, and the thymus, and faintly in the lung [14].
• Basal proliferation and mitogenic response to IGFs was diminished in NSD1(+/-) fibroblasts compared with NSD1(+/+) (basal, P=0.02; IGF-I, P<0.001; IGF-II, P=0.02) [15].
• About a half of Japanese Sotos syndrome patients carry a 2.2-Mb common deletion encompassing NSD1 and present with frequent brain, cardiovascular, or urinary tract anomalies [16].
• HepG2 is the only cell line tested that does not express ARA267-alpha [17].
• Northern blot analyses reveal that ARA267-alpha is expressed predominantly in the lymph node as 13- and 10-kilobase transcripts [17].

Associations of NSD1 with chemical compounds

• The NSD1 gene product is a SET-domain histone lysine methyltransferase that has previously been shown to interact with nuclear receptors [11].
• Mutations of the cysteine or histidine residues in the C2HR motif abolish the interaction of Nizp1 with NSD1 and compromise the ability of Nizp1 to repress transcription [11].
• Yeast two-hybrid and glutathione S-transferase pull-down assays show that both the N and C terminus of ARA267-alpha interact with the AR DNA- and ligand-binding domains [17].
• Luciferase and chloramphenicol acetyltransferase assays show that ARA267-alpha can enhance AR transactivation in a dihydrotestosterone-dependent manner in PC-3 and H1299 cells [17].
• Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between ARA267-alpha and DR6 [18].

Physical interactions of NSD1

• Androgen receptor coregulator ARA267-alpha interacts with death receptor-6 revealed by the yeast two-hybrid [18].
• Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization [19].

Other interactions of NSD1

• The reciprocal transcript, NSD1-NUP98, was also detected by reverse transcriptase--polymerase chain reaction [1].
• By using 3'--rapid amplification of complementary DNA ends (3'-RACE) polymerase chain reaction, we identified a chimeric messenger RNA that results in the in-frame fusion of NUP98 to a novel gene, NSD1 [1].
• The NSD1(+/+) patients did not differ from the reference, with the exception of the mean IGFBP-3 level (-1.3) [15].
• OBJECTIVE: To investigate the effect of nuclear receptor Su-var, 3-9, enhancer of zeste, trithorax (SET) domain-containing protein 1 (NSD1) gene alteration in patients with Sotos syndrome on plasma IGFs and IGF-binding proteins (IGFBPs), as well as on the IGF/IGFBP system activity at the tissue level [15].
• Identification and characterization of a novel androgen receptor coregulator ARA267-alpha in prostate cancer cells [17].

Analytical, diagnostic and therapeutic context of NSD1

• 3'-RACE-PCR identified an in-frame fusion between NUP98 and NSD1, which was confirmed by RT-PCR [2].
• A real-time quantitative PCR approach identified two patients with NSD1 deletions [20].
• OBJECTIVE: To develop a multiplex ligation dependent probe amplification (MLPA) assay to screen NSD1 for exonic deletions/duplications [21].
• Fluorescence in situ hybridization analyses demonstrated that neither the NSD1 nor MLL genes were involved in this case [22].
• One hybridoma (STO 171) reacted to platelet glycoprotein IIb (integrin alpha IIb) as determined by radioimmunoprecipitation and immunoblotting [23].

References