Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity.
OBJECTIVE
The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes.


METHODS
We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway.


RESULTS
All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The second group had more severe assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced.


CONCLUSIONS
These data indicate that collagen VI glycine mutations impair the assembly pathway in different ways and disease severity correlates with the assembly abnormality. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate-to-severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. This study thus provides an explanation for how different glycine mutations produce a spectrum of clinical severity.
Pace
Rishika A
RA
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia.
Peat
Rachel A
RA
Baker
Naomi L
NL
Zamurs
Laura
L
Mörgelin
Matthias
M
Irving
Melita
M
Adams
Naomi E
NE
Bateman
John F
JF
Mowat
David
D
Smith
Nicholas J C
NJ
Lamont
Phillipa J
PJ
Moore
Steven A
SA
Mathews
Katherine D
KD
North
Kathryn N
KN
Lamandé
Shireen R
SR
D000595:Amino Acid Sequence / Q000235:genetics; D002478:Cells, Cultured; D003095:Collagen Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D024142:Collagen Type VI / Q000096:biosynthesis / Q000235:genetics*; D003238:Connective Tissue / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005998:Glycine / Q000235:genetics*; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
D024142:Collagen Type VI; D012333:RNA, Messenger; D005998:Glycine