Autosomal recessive Bethlem myopathy.
BACKGROUND
Bethlem myopathy is a well-defined clinical entity among collagen VI disorders, featuring proximal muscle weakness and contractures of the fingers, wrists, and ankles. It is an early-onset, slowly progressive, and relatively mild disease, invariably associated to date with heterozygous dominant mutations in the 3 collagen VI genes. We have characterized the clinical, laboratory, and genetic features of autosomal recessive Bethlem myopathy in 2 unrelated patients.


METHODS
This study is based on clinical, histochemical, immunocytochemical, and electron microscope evaluation of the muscle and dermal fibroblasts, CT imaging of the muscles, and biochemical and molecular analysis.


RESULTS
Both patients carry a truncating COL6A2 mutation (Q819X; R366X) associated with missense changes in the partnering allele lying within the C2 domain of the alpha2(VI) chain (D871N; R843W-R830Q). They show decreased amounts of collagen VI in the basal lamina of muscle fibers and in dermal fibroblast cultures and altered behavior of collagen VI tetramers. Biochemical studies supported the pathogenic effect of identified amino acid substitutions, which involve strictly conserved residues.


CONCLUSIONS
The reported patients illustrate the occurrence of Bethlem myopathy with a recessive mode of inheritance. This observation completes the hereditary pattern in collagen VI myopathies with both Ullrich congenital muscular dystrophy and Bethlem myopathy underlined by either recessive or dominant effecting mutations. This finding has relevant implications for genetic counseling and molecular characterization of patients with Bethlem myopathy, as well as for genotype-phenotype correlations in collagen VI disorders.
Gualandi
F
F
Dipartimento di Medicina Sperimentale e Diagnostica, Sezione di Genetica Medica, Università di Ferrara, Ferrara, Italia 44100. gdf@unife.it
Urciuolo
A
A
Martoni
E
E
Sabatelli
P
P
Squarzoni
S
S
Bovolenta
M
M
Messina
S
S
Mercuri
E
E
Franchella
A
A
Ferlini
A
A
Bonaldo
P
P
Merlini
L
L
D000328:Adult; D002478:Cells, Cultured; D018389:Codon, Nonsense / Q000235:genetics; D003095:Collagen Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005973:Glutamine / Q000235:genetics; D006801:Humans; D008297:Male; D008854:Microscopy, Electron / Q000379:methods; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology* / Q000648:ultrastructure; D009135:Muscular Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology; D014057:Tomography, X-Ray Computed / Q000379:methods
D018389:Codon, Nonsense; D024142:Collagen Type VI; D005973:Glutamine