Fabiola Quintero-Rivera1, Celeste C Eno2, Christine Sutanto3, Kelly L Jones4,5, Małgorzata J M Nowaczyk6, Derek Wong7, Dawn Earl4, Ghayda Mirzaa8,9, Anita Beck4,9, Julian A Martinez-Agosto10,11,12. 1. Department of Pathology and Laboratory Medicine, University of California, Irvine (UCI), Irvine, CA, 92617, USA. fabiolaq@hs.ucla.edu. 2. Department of Academic Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. 3. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. 4. Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, 98105, USA. 5. Division of Medical Genetics and Metabolism, Children's Hospital of the King's Daughters, Norfolk, VA, 23507, USA. 6. Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8S4L8, Canada. 7. Division of Medical Genetics, Department of Pediatrics, UCLA, Los Angeles, CA, 90095, USA. 8. Center for Integrative Brain Research, University of Washington, Seattle, WA, 98195, USA. 9. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA. 10. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. JulianMartinez@mednet.ucla.edu. 11. Division of Medical Genetics, Department of Pediatrics, UCLA, Los Angeles, CA, 90095, USA. JulianMartinez@mednet.ucla.edu. 12. David Geffen School of Medicine, Neuropsychiatric Institute, University of California, Los Angeles, CA, 90095, USA. JulianMartinez@mednet.ucla.edu.
Abstract
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.
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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