Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene

Kurotaki, Naohiro; Harada, Naoki; Yoshiura, Koh-ichiro; Sugano, Sumio; Niikawa, Norio; Matsumoto, Naomichi

doi:10.1016/s0378-1119(01)00750-8

Cited by 83 publications

(85 citation statements)

References 15 publications

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“…The NSD1 protein contains a SET domain and other functional domains, including plant homeodomain and proline-tryptophantryptophan-proline domains, both of which are involved in a protein-protein interaction (8). NSD1 has histone methyltransferase activity, demonstrated by the use of a recombinant proteincontaining SET domain of NSD1 that has the ability to methylate the histone lysine residues H3-K36 and H4-K20 (9) and in the context of leukemia cells within the fusion protein NUP98-NSD1 to methylate H3-K36 in association with gene activation (10).…”

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confidence: 99%

Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma

Berdasco

Ropero

Setién

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

187

139

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Sotos syndrome is an autosomal dominant condition characterized by overgrowth resulting in tall stature and macrocephaly, together with an increased risk of tumorigenesis. The disease is caused by loss-of-function mutations and deletions of the nuclear receptor SET domain containing protein-1 (NSD1) gene, which encodes a histone methyltransferase involved in chromatin regulation. However, despite its causal role in Sotos syndrome and the typical accelerated growth of these patients, little is known about the putative contribution of NSD1 to human sporadic malignancies. Here, we report that NSD1 function is abrogated in human neuroblastoma and glioma cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also demonstrate that the epigenetic inactivation of NSD1 in transformed cells leads to the specifically diminished methylation of the histone lysine residues H4-K20 and H3-K36. The described phenotype is also observed in Sotos syndrome patients with NSD1 genetic disruption. Expression microarray data from NSD1-depleted cells, followed by ChIP analysis, revealed that the oncogene MEIS1 is one of the main NSD1 targets in neuroblastoma. Furthermore, we show that the restoration of NSD1 expression induces tumor suppressorlike features, such as reduced colony formation density and inhibition of cellular growth. Screening a large collection of different tumor types revealed that NSD1 CpG island hypermethylation was a common event in neuroblastomas and gliomas. Most importantly, NSD1 hypermethylation was a predictor of poor outcome in high-risk neuroblastoma. These findings highlight the importance of NSD1 epigenetic inactivation in neuroblastoma and glioma that leads to a disrupted histone methylation landscape and might have a translational value as a prognostic marker.cancer ͉ DNA methylation ͉ epigenetics ͉ histone ͉ overgrowth

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mentioning

confidence: 99%

Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma

Berdasco

Ropero

Setién

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

187

139

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“…1  In addition to acromegaly, the differential diagnosis list includes several syndromes such as Weaver, Beckwith-Wiedeman, Simpson-Golabi-Behmel, Cowden, Malan syndrome, Fragile X-syndrome (in males), or Marshall syndromes. 2  NSD1 (Nuclear receptor binding SET Domain protein 1) gene contains 23 exons located on 5q35, encoding a histone methyltransferase implicated in transcriptional regulation 3 . The variant we found was not previously described, but pathogenic mutations affecting the same cysteine residue have been reported 4 , strongly suggesting the pathogenicity of our variant.…”

Section: Discussionmentioning

confidence: 99%

Pseudoacromegaly - a differential diagnostic problem for acromegaly

Spencer¹,

Dahlqvist²,

Dang³

et al. 2016

EJEA

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“…NSD1 on chromosome 5q35 is the main causative gene of SS [5] and is expressed in several tissues including the brain, kidney, skeletal muscle, spleen, lung, and thymus [17]. The haploinsufficiency of NSD1 occurs in 60-90% of clinically diagnosed SS patients and can be transmitted in an autosomal dominant fashion, but over 95% of patients gain SS from de novo mutation without any family history [6].…”

Section: Discussionmentioning

confidence: 99%

A case of Sotos syndrome presented with end-stage renal disease due to the posterior urethral valve

Cho

Kang

et al. 2014

J Genet Med

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Sotos syndrome (SS, OMIM 117550) is characterized by prenatal and postnatal overgrowth with multiple congenital anomalies. However, there have been few cases of growth retardation caused by renal failure from infancy. We report a case of dysplasia of the bilateral kidneys with renal failure and poor postnatal growth. A 2-month-old boy visited the emergency room owing to poor oral intake and abdominal distension. He was born at the gestational age of 38 weeks with a birth weight of 4,180 g. After birth, he had feeding difficulty and abdominal distension. Upon physical examination, his height and weight were in less than the 3rd percentile, while his head circumference was in the 50th percentile on the growth curve. He also showed a broad and protruding forehead and high hairline. Blood laboratory tests showed severe azotemia; emergent hemodialysis was needed. Abdominal ultrasonography revealed bilateral renal dysplasia with multiple cysts and diffuse bladder wall thickening. A posterior urethral valve was suggested based on vesicoureterography and abdominal magnetic resonance findings. Results of a colon study to rule out congenital megacolon did not reveal any specific findings. The conventional karyotype of the patient was 46, XY. Array comparative genomic hybridization study revealed a chromosome 5q35 microdeletion including the NSD1 gene, based on which SS was diagnosed. We describe a case of SS presenting with end stage renal disease due to posterior urethral valve. The typical somatic overgrowth of SS in the postnatal period was not observed due to chronic renal failure that started in the neonatal period.

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Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene

Cited by 83 publications

References 15 publications

Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma

Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma

Pseudoacromegaly - a differential diagnostic problem for acromegaly

A case of Sotos syndrome presented with end-stage renal disease due to the posterior urethral valve

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