The Fly Homolog of SUPT16H, a Gene Associated With Neurodevelopmental Disorders, Is Required in a Cell-Autonomous Fashion for Cell Survival.

Authors

Mengqi Ma
Xi Zhang
Yiming Zheng
Shenzhao Lu
Xueyang Pan
Xiao Mao
Hongling Pan
Hyung-Lok Chung
Hua Wang
Hong Guo
Hugo J Bellen

Publication Date

3-6-2023

Journal

Human Molecular Genetics

DOI

10.1093/hmg/ddac259

PMID

36255738

PMCID

PMC9991001

PubMedCentral® Posted Date

10-18-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Cell Survival, Neurodevelopmental Disorders, Intellectual Disability, Epilepsy, Mutation, Missense, Brain Diseases, Drosophila

Abstract

SUPT16H encodes the large subunit of the FAcilitate Chromatin Transcription (FACT) complex, which functions as a nucleosome organizer during transcription. We identified two individuals from unrelated families carrying de novo missense variants in SUPT16H. The probands exhibit global developmental delay, intellectual disability, epilepsy, facial dysmorphism and brain structural abnormalities. We used Drosophila to characterize two variants: p.T171I and p.G808R. Loss of the fly ortholog, dre4, causes lethality at an early developmental stage. RNAi-mediated knockdown of dre4 in either glia or neurons causes severely reduced eclosion and longevity. Tissue-specific knockdown of dre4 in the eye or wing leads to the loss of these tissues, whereas overexpression of SUPT16H has no dominant effect. Moreover, expression of the reference SUPT16H significantly rescues the loss-of-function phenotypes in the nervous system as well as wing and eye. In contrast, expression of SUPT16H p.T171I or p.G808R rescues the phenotypes poorly, indicating that the variants are partial loss-of-function alleles. While previous studies argued that the developmental arrest caused by loss of dre4 is due to impaired ecdysone production in the prothoracic gland, our data show that dre4 is required for proper cell growth and survival in multiple tissues in a cell-autonomous manner. Altogether, our data indicate that the de novo loss-of-function variants in SUPT16H are indeed associated with developmental and neurological defects observed in the probands.

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