Dominant Missense Variants in SREBF2 Are Associated With Complex Dermatological, Neurological, and Skeletal Abnormalities

Authors

Matthew J Moulton
Kristhen Atala
Yiming Zheng
Debdeep Dutta
Dorothy K Grange
Wen-Wen Lin
Daniel J Wegner
Jennifer A Wambach
Angela L Duker
Michael B Bober
Lisa Kratz
Carol A Wise
Ila Oxendine
Anas Khanshour
Undiagnosed Diseases Network
Michael F Wangler
Shinya Yamamoto
F Sessions Cole
Jonathan Rios
Hugo J Bellen

Language

English

Publication Date

9-1-2024

Journal

Genetics in Medicine

DOI

10.1016/j.gim.2024.101174

PMID

38847193

PMCID

PMC12358889

PubMedCentral® Posted Date

8-19-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Purpose: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation.

Methods: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences of SREBF2 variants on SREBP pathway function.

Results: We observed reduced LD formation, endoplasmic reticulum expansion, accumulation of aberrant lysosomes, and deficits in SREBP2 target gene expression in fibroblasts from an affected individual, indicating that the SREBF2 variant inhibits SREBP pathway activation. Using our fly model, we discovered that SREBF2 variants fail to induce LD production and act in a dominant-negative manner, which can be rescued by overexpression of S1P.

Conclusion: Taken together, these data reveal a mechanism by which SREBF2 pathogenic variants that disrupt the S1P cleavage motif cause disease via dominant-negative antagonism of S1P, limiting the cleavage of S1P targets, including SREBP1 and SREBP2.

Keywords

Humans, Sterol Regulatory Element Binding Protein 2, Animals, Fibroblasts, Mutation, Missense, Male, Female, Lipid Droplets, Phenotype, Endoplasmic Reticulum, Serine Endopeptidases, Proprotein Convertases, Drosophila, Lipid droplet, S1P, SREBF1, SREBF2

Published Open-Access

yes

Recommended Citation

Moulton, Matthew J; Atala, Kristhen; Zheng, Yiming; et al., "Dominant Missense Variants in SREBF2 Are Associated With Complex Dermatological, Neurological, and Skeletal Abnormalities" (2024). Duncan NRI Faculty and Staff Publications. 140.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/140