Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.
In this study, we characterized five Ullrich scleroatonic muscular dystrophy patients (two Italians, one Belgian, and two Turks) with a clinical phenotype showing different degrees of severity, all carrying mutations localized in COL6A1. We sequenced the three entire COL6 complementary DNA. Three of five patients have recessive mutations: two patients (P1and P3) have homozygous single-nucleotide deletions, one in exon 9 and one in exon 22; one patient (P2) has a homozygous single-nucleotide substitution leading to a premature termination codon in exon 31. The nonsense mutation of P2 also causes a partial skipping of exon 31 with the formation of a premature termination codon in exon 32 in 15% of the total COL6A1 messenger RNA. The remaining two patients carry a heterozygous glycine substitution in exons 9 and 10 inside the triple-helix region; both are dominant mutations because the missense mutations are absent in the DNA of their respective parents. As for the three homozygous recessive mutations, the apparently healthy consanguineous parents all carry a heterozygous mutated allele. Here, for the first time, we report a genotype-phenotype correlation demonstrating that heterozygous glycine substitutions in the triple-helix domain of COL6A1 are dominant and responsible for a milder Ullrich scleroatonic muscular dystrophy phenotype, and that recessive mutations in COL6A1 correlate with more severe clinical and biochemical Ullrich scleroatonic muscular dystrophy phenotypes.
Giusti
Betti
B
Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy.
Lucarini
Laura
L
Pietroni
Valentina
V
Lucioli
Simona
S
Bandinelli
Brunella
B
Sabatelli
Patrizia
P
Squarzoni
Stefano
S
Petrini
Stefania
S
Gartioux
Corine
C
Talim
Beril
B
Roelens
Filip
F
Merlini
Luciano
L
Topaloglu
Haluk
H
Bertini
Enrico
E
Guicheney
Pascale
P
Pepe
Guglielmina
G
D000293:Adolescent; D015152:Blotting, Northern; D015153:Blotting, Western / Q000379:methods; D002648:Child; D002675:Child, Preschool; D024142:Collagen Type VI / Q000235:genetics* / Q000378:metabolism; D003240:Connective Tissue Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000648:ultrastructure; D004252:DNA Mutational Analysis; D018076:DNA, Complementary; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique / Q000379:methods; D005808:Genes, Recessive; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D016253:Microscopy, Immunoelectron / Q000379:methods; D008970:Molecular Weight; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D044465:White People
D024142:Collagen Type VI; D018076:DNA, Complementary; D012333:RNA, Messenger; D005998:Glycine