Early onset collagen VI myopathies: Genetic and clinical correlations.
OBJECTIVE
Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations.


METHODS
Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA.


RESULTS
ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation).


CONCLUSIONS
This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials.
Briñas
Laura
L
Inserm, U582, Paris, France.
Richard
Pascale
P
Quijano-Roy
Susana
S
Gartioux
Corine
C
Ledeuil
Céline
C
Lacène
Emmanuelle
E
Makri
Samira
S
Ferreiro
Ana
A
Maugenre
Svetlana
S
Topaloglu
Haluk
H
Haliloglu
Göknur
G
Pénisson-Besnier
Isabelle
I
Jeannet
Pierre-Yves
PY
Merlini
Luciano
L
Navarro
Carmen
C
Toutain
Annick
A
Chaigne
Denys
D
Desguerre
Isabelle
I
de Die-Smulders
Christine
C
Dunand
Murielle
M
Echenne
Bernard
B
Eymard
Bruno
B
Kuntzer
Thierry
T
Maincent
Kim
K
Mayer
Michèle
M
Plessis
Ghislaine
G
Rivier
François
F
Roelens
Filip
F
Stojkovic
Tanya
T
Taratuto
Ana Lía
AL
Lubieniecki
Fabiana
F
Monges
Soledad
S
Tranchant
Christine
C
Viollet
Louis
L
Romero
Norma B
NB
Estournet
Brigitte
B
Guicheney
Pascale
P
Allamand
Valérie
V
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D024143:Collagen Type VII / Q000235:genetics* / Q000378:metabolism*; D005060:Europe; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005820:Genetic Testing / Q000379:methods; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D013223:Statistics as Topic; D055815:Young Adult
D024143:Collagen Type VII; D005998:Glycine