English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

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

Kornak, U., Saha, N., Keren, B., Neumann, A., Taylor Tavares, A. L., Piard, J., et al. (2022). Alternative splicing of BUD13 determines the severity of a developmental disorder with lipodystrophy and progeroid features. GENETICS IN MEDICINE, 24(9), 1927-1940. doi:10.1016/j.gim.2022.05.004.

Item is

Basic

show hide
Genre: Journal Article

Files

show Files

Locators

show

Creators

show
hide
 Creators:
Kornak, Uwe1, Author           
Saha, Namrata, Author
Keren, Boris, Author
Neumann, Alexander, Author
Taylor Tavares, Ana Lisa , Author
Piard, Juliette, Author
Kopp, Johannes, Author
Rodrigues Alves, João Guilherme , Author
de los Santos, Miguel Rodríguez , Author
El Choubassi, Naji, Author
Ehmke, Nadja, Author
Jäger, Marten, Author
Spielmann, Malte2, Author           
Pantel, Jean Tori, Author
Lejeune, Elodie, Author
Fauler, Beatrix3, Author           
Mielke, Thorsten3, Author           
Hecht, Jochen, Author
Meierhofer, David4, Author           
Strom, Tim M. , Author
Laugel, Vincent, AuthorBrice, Alexis, AuthorMundlos, Stefan1, Author           Bertoli-Avella, Aida, AuthorBauer, Peter, AuthorHeyd, Florian , AuthorBoute, Odile , AuthorDupont, Juliette , AuthorDepienne, Christel , AuthorVan Maldergem, Lionel , AuthorFischer-Zirnsak, Björn , Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014183              
3Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
4Mass Spectrometry Facility (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

Content

show
hide
Free keywords: -
 Abstract: 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.

Details

show
hide
Language(s): eng - English
 Dates: 2022-06-072022-09
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.gim.2022.05.004
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: GENETICS IN MEDICINE
  Other : Genet. Med.
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Baltimore, MD : Williams & Wilkins
Pages: - Volume / Issue: 24 (9) Sequence Number: - Start / End Page: 1927 - 1940 Identifier: ISSN: 1098-3600
CoNE: https://pure.mpg.de/cone/journals/resource/954925610933