Alternative splicing of BUD13 determines the severity of a developmental disorder with lipodystrophy and progeroid features

Uwe Kornak*, Namrata Saha, Boris Keren, Alexander Neumann, Ana Lisa Taylor Tavares, Juliette Piard*, Johannes Kopp, João Guilherme Rodrigues Alves, Miguel Rodríguez de los Santos, Naji El Choubassi, Nadja Ehmke, Marten Jäger, Malte Spielmann, Jean Tori Pantel, Elodie Lejeune, Beatrix Fauler, Thorsten Mielke, Jochen Hecht, David Meierhofer, Tim M. StromVincent Laugel, Alexis Brice, Stefan Mundlos, Aida Bertoli-Avella, Peter Bauer, Florian Heyd, Odile Boute*, Juliette Dupont*, Christel Depienne, Lionel Van Maldergem, Björn Fischer-Zirnsak*

*Korrespondierende/r Autor/-in für diese Arbeit


Purpose: In this study we aimed to identify the molecular genetic cause of a progressive multisystem disease with prominent lipodystrophy. Methods: In total, 5 affected individuals were investigated using exome sequencing. Dermal fibroblasts were characterized using RNA sequencing, proteomics, immunoblotting, immunostaining, and electron microscopy. Subcellular localization and rescue studies were performed. Results: We identified a lipodystrophy phenotype with a typical facial appearance, corneal clouding, achalasia, progressive hearing loss, and variable severity. Although 3 individuals showed stunted growth, intellectual disability, and died within the first decade of life (A1, A2, and A3), 2 are adults with normal intellectual development (A4 and A5). All individuals harbored an identical homozygous nonsense variant affecting the retention and splicing complex component BUD13. The nucleotide substitution caused alternative splicing of BUD13 leading to a stable truncated protein whose expression positively correlated with disease expression and life expectancy. In dermal fibroblasts, we found elevated intron retention, a global reduction of spliceosomal proteins, and nuclei with multiple invaginations, which were more pronounced in A1, A2, and A3. Overexpression of both BUD13 isoforms normalized the nuclear morphology. Conclusion: Our results define a hitherto unknown syndrome and show that the alternative splice product converts a loss-of-function into a hypomorphic allele, thereby probably determining the severity of the disease and the survival of affected individuals.

ZeitschriftGenetics in Medicine
Seiten (von - bis)1927-1940
PublikationsstatusVeröffentlicht - 09.2022

Strategische Forschungsbereiche und Zentren

  • Querschnittsbereich: Medizinische Genetik