5q35 duplication presents with psychiatric and undergrowth phenotypes mediated by NSD1 overexpression and mTOR signaling downregulation. Hum Genet 2021 Apr;140(4):681-690
Date
01/04/2021Pubmed ID
33389145Pubmed Central ID
PMC8733961DOI
10.1007/s00439-020-02240-5Scopus ID
2-s2.0-85098529732 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
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.
Author List
Quintero-Rivera F, Eno CC, Sutanto C, Jones KL, Nowaczyk MJM, Wong D, Earl D, Mirzaa G, Beck A, Martinez-Agosto JAAuthor
Kelly Jones MD Assistant Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Animals
Caspases
Cell Death
Child
Child, Preschool
Chromosome Disorders
Chromosomes, Human, Pair 5
Down-Regulation
Drosophila melanogaster
Female
Gene Duplication
Histone-Lysine N-Methyltransferase
Humans
Leucine
Male
Pedigree
Phenotype
Signal Transduction
TOR Serine-Threonine Kinases
Young Adult
