Journal
HUMAN GENETICS
Volume 140, Issue 4, Pages 681-690Publisher
SPRINGER
DOI: 10.1007/s00439-020-02240-5
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Funding
- March of Dimes [6-FY12-324]
- UCLA Children's Discovery Institute, UCLA CART (NIH/NICHD) [P50-HD-055784]
- UCLA Department of Pathology translational research fund
- NIH/NIGMS [5T32GM007454]
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NSD1 plays a critical role in microduplication 5q35 syndrome, potentially affecting growth and psychiatric phenotypes by altering mTOR pathway signaling. The study also suggests that leucine supplementation may serve as a potential therapeutic approach to ameliorate the symptoms.
Purpose 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. Methods 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. Results 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. Conclusion 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.
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