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5q35 duplication presents with psychiatric and undergrowth phenotypes mediated by NSD1 overexpression and mTOR signaling downregulation.
- Source :
-
Human genetics [Hum Genet] 2021 Apr; Vol. 140 (4), pp. 681-690. Date of Electronic Publication: 2021 Jan 03. - Publication Year :
- 2021
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Adolescent
Adult
Animals
Caspases metabolism
Cell Death
Child
Child, Preschool
Down-Regulation
Drosophila melanogaster
Female
Humans
Leucine metabolism
Leucine pharmacology
Male
Pedigree
Phenotype
Signal Transduction
Young Adult
Chromosome Disorders genetics
Chromosomes, Human, Pair 5
Gene Duplication
Histone-Lysine N-Methyltransferase genetics
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1432-1203
- Volume :
- 140
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 33389145
- Full Text :
- https://doi.org/10.1007/s00439-020-02240-5