Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers-Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix.

Abstract

PURPOSE:

To date, heterozygous or homozygous COL12A1 variants have been reported in 13 patients presenting with a clinical phenotype overlapping with collagen VI-related myopathies and Ehlers-Danlos syndrome (EDS). The small number of reported patients limits thorough investigation of this newly identified syndrome, currently coined as myopathic EDS.

METHODS:

DNA from 78 genetically unresolved patients fulfilling the clinical criteria for myopathic EDS was sequenced using a next-generation panel of COL12A1, COL6A1, COL6A2, and COL6A3.

RESULTS:

Among this cohort, we identified four pathogenic heterozygous in-frame exon skipping (∆) defects in COL12A1, clustering to the thrombospondin N-terminal region and the adjacent collagenous domain (Δ52, Δ53, Δ54, and Δ56 respectively), one heterozygous COL12A1 arginine-to-cysteine substitution of unclear significance (p.(Arg1863Cys)), and compound heterozygous pathogenic COL6A1 variants (c.[98-6G>A];[301C>T]) in one proband. Variant-specific intracellular accumulation of collagen XII chains, extracellular overmodification of the long isoform and near-absence of the short isoform of collagen XII, and extracellular decrease of decorin and tenascin-X were observed for the COL12A1 variants. In contrast, the COL6A1 variants abolished collagen VI and V deposition and increased tenascin-X levels.

CONCLUSION:

Our data further support the significant clinical overlap between myopathic EDS and collagen VI-related myopathies, and emphasize the variant-specific consequences of collagen XII defects.

• Authors: Sarah Delbaere, Tibbe Dhooge, Delfien Syx, Florence Petit, Nathalie Goemans, Anne Destrée, Olivier Vanakker, Riet De Rycke, Sofie Symoens, Fransiska Malfait
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 22 Issue 1 Pg. 112-123 (01 2020) ISSN: 1530-0366 [Electronic] United States
• PMID: 31273343 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• COL12A1 protein, human
• Col6a1 protein, human
• Collagen Type V
• Collagen Type VI
• Collagen Type XII
• DCN protein, human
• Decorin
• Tenascin
• tenascin X

Topics

• Adolescent
• Adult
• Cells, Cultured
• Child
• Child, Preschool
• Collagen Type V (metabolism)
• Collagen Type VI (chemistry, genetics)
• Collagen Type XII (chemistry, genetics)
• Decorin (metabolism)
• Ehlers-Danlos Syndrome (genetics, metabolism)
• Extracellular Matrix (metabolism)
• Female
• High-Throughput Nucleotide Sequencing (methods)
• Humans
• Male
• Muscular Diseases (genetics, metabolism)
• Mutation
• Pedigree
• Protein Domains
• Sequence Analysis, DNA
• Tenascin (metabolism)