Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype.

Abstract

OBJECTIVE:

To investigate the molecular basis of autosomal dominant limb-girdle muscular dystrophy (AD-LGMD) in three large new families.

METHODS AND RESULTS:

Genome-wide linkage was performed to show that the causative gene in all three families localized to chromosome 21q22.3 (Zmax = 10.3; theta = 0). This region contained the collagen VI alpha1 and alpha2 genes, which have been previously shown to harbor mutations causing a relatively mild congenital myopathy with contractures (Bethlem myopathy). Screening of the collagen VI alpha1 and alpha2 genes revealed novel, causative mutations in each family (COL6A1-K121R, G341D; COL6A2-D620N); two of these mutations were in novel regions of the proteins not previously associated with disease. Collagen VI is a ubiquitously expressed component of connective tissue; however, both limb-girdle muscular dystrophy and Bethlem myopathy patients show symptoms restricted to skeletal muscle. To address the muscle-specific symptoms resulting from collagen VI mutations, the authors studied three patient muscle biopsies at the molecular level (protein expression). A marked reduction of laminin beta1 protein in the myofiber basal lamina in all biopsies was found, although this protein was expressed normally in the neighboring capillary basal laminae.

CONCLUSIONS:

The authors' studies widen the clinical spectrum of Bethlem myopathy and suggest collagen VI etiology should be investigated in dominant limb-girdle muscular dystrophy. The authors hypothesize that collagen VI mutations lead to muscle-specific defects of the basal lamina, and may explain the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy patients with collagen VI mutations.

• Authors: P C Scacheri, E M Gillanders, S H Subramony, V Vedanarayanan, C A Crowe, N Thakore, M Bingler, E P Hoffman
• Journal: Neurology (Neurology) Vol. 58 Issue 4 Pg. 593-602 (Feb 26 2002) ISSN: 0028-3878 [Print] United States
• PMID: 11865138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Collagen Type VI

Topics

• Adolescent
• Adult
• Aged
• Child
• Chromosomes, Human, Pair 21 (genetics)
• Collagen Type VI (genetics)
• Female
• Humans
• Lod Score
• Male
• Middle Aged
• Muscle, Skeletal (metabolism, pathology)
• Muscular Diseases (genetics, metabolism, pathology)
• Muscular Dystrophies (genetics, metabolism, pathology)
• Mutation (genetics)
• Pedigree
• Phenotype