TY - JOUR
T1 - Alternative splicing of BUD13 determines the severity of a developmental disorder with lipodystrophy and progeroid features
AU - Kornak, Uwe
AU - Saha, Namrata
AU - Keren, Boris
AU - Neumann, Alexander
AU - Taylor Tavares, Ana Lisa
AU - Piard, Juliette
AU - Kopp, Johannes
AU - Rodrigues Alves, João Guilherme
AU - Rodríguez de los Santos, Miguel
AU - El Choubassi, Naji
AU - Ehmke, Nadja
AU - Jäger, Marten
AU - Spielmann, Malte
AU - Pantel, Jean Tori
AU - Lejeune, Elodie
AU - Fauler, Beatrix
AU - Mielke, Thorsten
AU - Hecht, Jochen
AU - Meierhofer, David
AU - Strom, Tim M.
AU - Laugel, Vincent
AU - Brice, Alexis
AU - Mundlos, Stefan
AU - Bertoli-Avella, Aida
AU - Bauer, Peter
AU - Heyd, Florian
AU - Boute, Odile
AU - Dupont, Juliette
AU - Depienne, Christel
AU - Van Maldergem, Lionel
AU - Fischer-Zirnsak, Björn
N1 - Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85131605137&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2022.05.004
DO - 10.1016/j.gim.2022.05.004
M3 - Journal articles
C2 - 35670808
AN - SCOPUS:85131605137
SN - 1098-3600
VL - 24
SP - 1927
EP - 1940
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 9
ER -