COL6A1 – Ullrich congenital muscular dystrophy

Collagen VI-related dystrophies encompass a spectrum from the severe Ullrich congenital muscular dystrophy (UCMD) to the milder Bethlem myopathy, all caused by pathogenic variants in the COL6A1 gene (HGNC:2211). UCMD (MONDO:0000355) manifests with congenital muscle weakness, proximal joint contractures, distal hyperlaxity, and early respiratory insufficiency, reflecting disrupted extracellular matrix integrity around myofibers (MONDO:0000355).

Pathogenic COL6A1 variants underlie UCMD by two mechanisms: autosomal recessive loss-of-function and dominant-negative in-frame alterations. Bi-allelic splice-site, nonsense, and frameshift mutations result in complete loss of functional α1(VI) chains, while heterozygous de novo dominant-negative in-frame insertions disrupt tetramer assembly. A recurrent deep intronic variant (c.930+189C>T) acts dominantly via pseudoexon insertion in 44 unrelated UCMD patients (PMID:38585825).

Segregation evidence includes three affected siblings homozygous for a novel splice-site variant c.98-1G>C in a consanguineous Malian family (PMID:39523858) and two adult siblings compound heterozygous for c.1770delG and p.Arg830Trp in exon 28 (PMID:19884007). Parents are asymptomatic carriers in recessive pedigrees, confirming autosomal recessive inheritance. Overall, five additional affected relatives have been documented with segregating COL6A1 variants.

The COL6A1 variant spectrum in UCMD includes c.904G>A (p.Gly302Arg) identified in a sporadic case (PMID:24855628), multi-exon deletions, glycine substitutions within the Gly-X-Y triple-helix, canonical splice-site mutations, and deep intronic events. Recurrent dominant variants cluster in the N-terminal triple helix and cause dominant negative effects, whereas recessive variants are distributed throughout the gene.

Functional assays corroborate pathogenicity: immunohistochemistry in muscle biopsies shows reduced collagen VI at the basement membrane in UCMD patients (PMID:12011280); patient fibroblasts demonstrate impaired secretion and extracellular aggregation of mutant α1(VI) chains (PMID:35946603); exon-skipping antisense oligonucleotides restore functional microfibrils in c.930+189C>T patient fibroblasts (PMID:32585628); and a humanized mouse model carrying c.930+189C>T recapitulates the splicing defect and muscle weakness (PMID:38585878).

No major conflicting reports have refuted the COL6A1–UCMD association. A subset of UCMD-like cases without COL6A1 involvement indicates genetic heterogeneity, but the preponderance of evidence supports a definitive role for COL6A1.

Integration of genetic segregation, variant diversity, and functional concordance across cell and animal models provides a coherent narrative establishing COL6A1 as a definitive UCMD gene. This robust evidence base enables accurate molecular diagnosis, informs recurrence risk counseling, and guides the development of targeted splice-modulating therapies.

Key Take-home: COL6A1 variants underlie UCMD via recessive loss-of-function and dominant-negative mechanisms; comprehensive genetic testing coupled with emerging antisense and editing therapies offers immediate clinical utility for diagnosis and future treatment.

References

• Neurology • 2002 • Collagen VI involvement in Ullrich syndrome: a clinical, genetic, and immunohistochemical study PMID:12011280
• Neuromuscular disorders : NMD • 2009 • Autosomal recessive inheritance of classic Bethlem myopathy. PMID:19884007
• Molecular genetics & genomic medicine • 2024 • A Novel Splice Site Variant in COL6A1 Causes Ullrich Congenital Muscular Dystrophy in a Consanguineous Malian Family. PMID:39523858
• medRxiv : the preprint server for health sciences • 2024 • The recurrent deep intronic pseudoexon-inducing variant COL6A1 c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy. PMID:38585825
• Molecular therapy. Nucleic acids • 2020 • Exon-Skipping Oligonucleotides Restore Functional Collagen VI by Correcting a Common COL6A1 Mutation in Ullrich CMD. PMID:32585628
• bioRxiv • 2024 • A humanized knock-in Col6a1 mouse recapitulates a deep-intronic splice-activating variant. PMID:38585878
• Disease models & mechanisms • 2022 • Collagen VI deficiency causes behavioral abnormalities and cortical dopaminergic dysfunction. PMID:35946603

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