Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder
Geert R Mortiera, MaryAnn Weisb, Lieve Nuytincka, Lily M Kingc, Douglas J Wilkind, Anne De Paepea, Ralph S Lachmanc, David L Rimoinc, David R Eyreb, Daniel H Cohnc
a Department of
Medical Genetics, University Hospital of Gent, De Pintelaan 185, B-9000
Gent, Belgium, b Department of Orthopedics, University of
Washington, Seattle, WA, USA, c Steven Spielberg Pediatric Research Center,
Burns & Allen Cedars-Sinai Research Institute and Departments of
Pediatrics and Radiology, UCLA School of Medicine, Los Angeles, CA, USA, d Medical
Genetics Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, MD, USA
Correspondence to: Dr Mortier
Revised version received 12 July 1999;
Accepted for publication 5 August
1999
Achondrogenesis II-hypochondrogenesis and severe
spondyloepiphyseal dysplasia congenita (SEDC) are lethal forms of
dwarfism caused by dominant mutations in the type II collagen gene
(COL2A1). To identify the underlying defect
in seven cases with this group of conditions, we used the combined
strategy of cartilage protein analysis and
COL2A1 mutation analysis. Overmodified type
II collagen and the presence of type I collagen was found in the
cartilage matrix of all seven cases. Five patients were heterozygous
for a nucleotide change that predicted a glycine substitution in the triple helical domain (G313S, G517V, G571A, G910C, G943S). In all five
cases, analysis of cartilage type II collagen suggested incorporation
of the abnormal 
1(II) chain in the extracellular collagen trimers.
The G943S mutation has been reported previously in another unrelated
patient with a strikingly similar phenotype, illustrating the possible
specific effect of the mutation. The radiographically less severely
affected patient was heterozygous for a 4 bp deletion in the splice
donor site of intron 35, likely to result in aberrant splicing. One
case was shown to be heterozygous for a single nucleotide change
predicted to result in a T1191N substitution in the carboxy-propeptide
of the pro1(II) collagen chain. Study of the clinical, radiographic,
and morphological features of the seven cases supports evidence for a
phenotypic continuum between achondrogenesis II-hypochondrogenesis and
lethal SEDC and suggests a relationship between the amount of type I collagen in the cartilage and the severity of the phenotype.
Keywords: type II collagen disorders; achondrogenesis II-hypochondrogenesis; spondyloepiphyseal dysplasia congenita; COL2A1
© 2000 by J Med Genet
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