Department of Pathology and Laboratory Medicine, University of California, Irvine (UCI), Irvine, CA, 92617, USA.
Department of Academic Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
Hum Genet. 2021 Apr;140(4):681-690. doi: 10.1007/s00439-020-02240-5. Epub 2021 Jan 3.
Nuclear receptor binding SET domain protein 1, NSD1, encodes a histone methyltransferase H3K36. NSD1 is responsible for the phenotype of the reciprocal 5q35.2q35.3 microdeletion-microduplication syndromes. We expand the phenotype and demonstrate the functional role of NSD1 in microduplication 5q35 syndrome.
Through an international collaboration, we report nine new patients, contributing to the emerging phenotype, highlighting psychiatric phenotypes in older affected individuals. Focusing specifically on the undergrowth phenotype, we have modeled the effects of Mes-4/NSD overexpression in Drosophila melanogaster.
The individuals (including a family) from diverse backgrounds with duplications ranging in size from 0.6 to 4.5 Mb, have a consistent undergrowth phenotype. Mes-4 overexpression in the developing wing causes undergrowth, increased H3K36 methylation, and increased apoptosis. We demonstrate that altering the levels of insulin receptor (IR) rescues the apoptosis and the wing undergrowth phenotype, suggesting changes in mTOR pathway signaling. Leucine supplementation rescued Mes-4/NSD induced cell death, demonstrating decreased mTOR signaling caused by NSD1.
Given that we show mTOR inhibition as a likely mechanism and amelioration of the phenotype by leucine supplementation in a fly model, we suggest further studies should evaluate the therapeutic potential of leucine or branched chain amino acids as an adjunct possible treatment to ameliorate human growth and psychiatric phenotypes and propose inclusion of 5q35-microduplication as part of the differential diagnosis for children and adults with delayed bone age, short stature, microcephaly, developmental delay, and psychiatric phenotypes.
核受体结合 SET 域蛋白 1（NSD1）编码一种组蛋白甲基转移酶 H3K36。NSD1 负责导致相互的 5q35.2q35.3 微缺失-微重复综合征的表型。我们扩展了表型，并证明了 NSD1 在微重复 5q35 综合征中的功能作用。
通过国际合作，我们报告了 9 名新患者，为新兴表型做出了贡献，突出了老年受影响个体的精神表型。我们特别关注生长迟缓表型，在黑腹果蝇中模拟 Mes-4/NSD 过表达的影响。
来自不同背景的个体（包括一个家庭），其重复大小从 0.6 到 4.5 Mb 不等，具有一致的生长迟缓表型。在发育中的翅膀中过表达 Mes-4 会导致生长迟缓、H3K36 甲基化增加和细胞凋亡增加。我们证明改变胰岛素受体（IR）的水平可以挽救细胞凋亡和翅膀生长迟缓表型，表明 mTOR 途径信号发生变化。亮氨酸补充可挽救 Mes-4/NSD 诱导的细胞死亡，表明 NSD1 导致 mTOR 信号降低。
鉴于我们表明 mTOR 抑制是一种可能的机制，并且亮氨酸补充在果蝇模型中改善了表型，我们建议进一步研究应评估亮氨酸或支链氨基酸作为辅助治疗的潜在治疗潜力，以改善人类生长和精神表型，并建议将 5q35 微重复纳入儿童和成人骨龄延迟、身材矮小、小头症、发育迟缓以及精神表型的鉴别诊断的一部分。
