Molecular consequences of dominant Bethlem myopathy collagen VI mutations.
OBJECTIVE
Dominant mutations in the three collagen VI genes cause Bethlem myopathy, a disorder characterized by proximal muscle weakness and commonly contractures of the fingers, wrists, and ankles. Although more than 20 different dominant mutations have been identified in Bethlem myopathy patients, the biosynthetic consequences of only a subset of these have been studied, and in many cases, the pathogenic mechanisms remain unknown.


METHODS
We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly.


RESULTS
Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal amount of alpha1(VI) messenger RNA and reduced amounts of collagen VI protein. Two patients had a previously reported mutation causing skipping of COL6A1 exon 14, and three patients had novel mutations leading to in-frame deletions toward the N-terminal end of the triple-helical domain. These mutations have different and complex effects on collagen VI intracellular and extracellular assembly. Two patients had single amino acid substitutions in the A-domains of COL6A2 and COL6A3. Collagen VI intracellular and extracellular assembly was normal in one of these patients.


CONCLUSIONS
The key to dissecting the pathogenic mechanisms of collagen VI mutations lies in detailed analysis of collagen VI biosynthesis and assembly. The majority of mutations result in secretion and deposition of structurally abnormal collagen VI. However, one A-domain mutation had no detectable effect on assembly, suggesting that it acts by compromising collagen VI interactions in the extracellular matrix of muscle.
Baker
Naomi L
NL
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
Mörgelin
Matthias
M
Pace
Rishika A
RA
Peat
Rachel A
RA
Adams
Naomi E
NE
Gardner
R J McKinlay
RJ
Rowland
Lewis P
LP
Miller
Geoffrey
G
De Jonghe
Peter
P
Ceulemans
Berten
B
Hannibal
Mark C
MC
Edwards
Matthew
M
Thompson
Elizabeth M
EM
Jacobson
Richard
R
Quinlivan
Ros C M
RC
Aftimos
Salim
S
Kornberg
Andrew J
AJ
North
Kathryn N
KN
Bateman
John F
JF
Lamandé
Shireen R
SR
D000328:Adult; D003095:Collagen Diseases / Q000235:genetics*; D024142:Collagen Type VI / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D024142:Collagen Type VI