Freiburg, Carolin D;
Solomon-Degefa, Herimela;
Freiburg, Patrick;
Mörgelin, Matthias;
Bolduc, Véronique;
Schmitz, Sebastian;
Ala, Pierpaolo;
... Wagener, Raimund; + view all
(2023)
The UCMD-Causing COL6A1 (c:930 + 189C > T) Intron Mutation Leads to the Secretion and Aggregation of Single Mutated Collagen VI α1 Chains.
Human Mutation
, 2023
, Article 6892763. 10.1155/2023/6892763.
Preview |
Text
6892763.pdf - Published Version Download (6MB) | Preview |
Abstract
Collagen VI is a unique member of the collagen family. Its assembly is a complex multistep process and the vulnerability of the process is manifested in muscular diseases. Mutations in COL6A1, COL6A2, and COL6A3 lead to the severe Ullrich Congenital Muscular Dystrophy (UCMD) and a spectrum of disease of varying severity including the milder Bethlem muscular dystrophy. The recently identified dominant intronic mutation in COL6A1 ( <math xmlns="http://www.w3.org/1998/Math/MathML" id="M2"> <mi>c</mi> <mo>.</mo> <mn>930</mn> <mo>+</mo> <mn>189</mn> <mi>C</mi> <mo>></mo> <mi>T</mi> </math> ) leads to the partial in-frame insertion of a pseudoexon between exon 11 and exon 12. The pseudoexon is translated into 24 amino acid residues in the N-terminal region of the triple helix and results in the interruption of the typical G-X-Y motif. This recurrent de novo mutation leads to UCMD with a severe progression within the first decade of life. Here, we demonstrate that a mutation-specific antibody detects the mutant chain colocalizing with wild type collagen VI in the endomysium in patient muscle. Surprisingly, in the cell culture of patient dermal fibroblasts, the mutant chain is secreted as a single α chain, while in parallel, normal collagen VI tetramers are assembled with the wild-type α1 chain. The mutant chain cannot be incorporated into collagen VI tetramers but forms large aggregates in the extracellular matrix that may retain the ability to interact with collagen VI and potentially with other molecules. Also, α1 chain-deficient WI-26 VA4 cells transfected with the mutant α1 chain do not assemble collagen VI tetramers but, instead, form aggregates. Interestingly, both the wild type and the mutant single α1 chains form amorphous aggregates when expressed in HEK293 cells in the absence of α2 and α3 chains. The detection of aggregated, assembly incompetent, mutant collagen VI α1 chains provides novel insights into the disease pathophysiology of UCMD patients with the COL6A1 ( <math xmlns="http://www.w3.org/1998/Math/MathML" id="M3"> <mi>c</mi> <mo>.</mo> <mn>930</mn> <mo>+</mo> <mn>189</mn> <mi>C</mi> <mo>></mo> <mi>T</mi> </math> ) mutation.
| Type: | Article |
|---|---|
| Title: | The UCMD-Causing COL6A1 (c:930 + 189C > T) Intron Mutation Leads to the Secretion and Aggregation of Single Mutated Collagen VI α1 Chains |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1155/2023/6892763 |
| Publisher version: | https://doi.org/10.1155/2023/6892763 |
| Language: | English |
| Additional information: | Copyright © 2023 Carolin D. Freiburg et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10177022 |
Archive Staff Only
 |
View Item |
