Loss-of-function variants affecting the STAGA complex component SUPT7L cause a developmental disorder with generalized lipodystrophy.
Johannes KoppLeonard A KochHristiana LyubenovaOliver KüchlerManuel HoltgreweAndranik IvanovChristele DubourgÉrika Dayane Leal RodriguesSebastian BrachsStefan MundlosNadja EhmkeDominik SeelowMélanie FradinUwe KornakBjörn Fischer-ZirnsakPublished in: Human genetics (2024)
Generalized lipodystrophy is a feature of various hereditary disorders, often leading to a progeroid appearance. In the present study we identified a missense and a frameshift variant in a compound heterozygous state in SUPT7L in a boy with intrauterine growth retardation, generalized lipodystrophy, and additional progeroid features. SUPT7L encodes a component of the transcriptional coactivator complex STAGA. By transcriptome sequencing, we showed the predicted missense variant to cause aberrant splicing, leading to exon truncation and thereby to a complete absence of SUPT7L in dermal fibroblasts. In addition, we found altered expression of genes encoding DNA repair pathway components. This pathway was further investigated and an increased rate of DNA damage was detected in proband-derived fibroblasts and genome-edited HeLa cells. Finally, we performed transient overexpression of wildtype SUPT7L in both cellular systems, which normalizes the number of DNA damage events. Our findings suggest SUPT7L as a novel disease gene and underline the link between genome instability and progeroid phenotypes.
Keyphrases
- dna damage
- dna repair
- genome wide
- oxidative stress
- copy number
- induced apoptosis
- cell cycle arrest
- gene expression
- single cell
- poor prognosis
- dna damage response
- intellectual disability
- dna methylation
- extracellular matrix
- transcription factor
- crispr cas
- cell proliferation
- machine learning
- rna seq
- autism spectrum disorder
- brain injury
- mass spectrometry
- signaling pathway
- high resolution
- cerebral ischemia
- endoplasmic reticulum stress
- subarachnoid hemorrhage
- wound healing