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5q35 duplication presents with psychiatric and undergrowth phenotypes mediated by NSD1 overexpression and mTOR signaling downregulation.

Authors :
Quintero-Rivera F
Eno CC
Sutanto C
Jones KL
Nowaczyk MJM
Wong D
Earl D
Mirzaa G
Beck A
Martinez-Agosto JA
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.

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