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A large family with dominantly inherited rhegmatogenous retinal detachment, premature arthropathy, and development of phalangeal epiphyseal dysplasia, resulting in brachydactyly was linked to COL2A1, the gene encoding pro[alpha]1 (II) collagen. Mutational analysis of the gene by exon sequencing identified a novel mutation in the C-propeptide region of the molecule. The glycine to aspartic acid change occurred in a region that is highly conserved in all fibrillar collagen molecules. The resulting phenotype does not fit easily into pre-existing subgroups of the type II collagenopathies, which includes spondyloepiphyseal dysplasia, and the Kniest, Strudwick, and Stickler dysplasias.
The inherited disorders resulting from mutations in COL2A1, the gene for pro[alpha]1 (II) collagen form a spectrum of phenotypes, which are collectively known as the type II collagenopathies. (1) These range from the lethal or perinatally lethal disorders achondrogenesis II and hypochondrogenesis, (2 3) through disproportionate dwarfisms, which include spondyloepiphyseal dysplasia congenita (SEDC), the Strudwick type of spondyloepimetaphyseal dysplasia (SEMD), and Kniest dysplasia. (4-9) At the milder end of the spectrum of type II collagenopathies is Stickler syndrome or arthro-ophthalmopathy. (10) Other disorders include familial osteoarthritis (11) and a predominantly ocular form of Stickler syndrome. (12)
Nine different genes code for the human fibrillar collagen molecules, (13) which comprise types I, II, III, V. and XI, and all are synthesised as propeptides. The carboxyl propeptide region of each molecule is required for [alpha] chain association, which then proceed to zip up from the C to N terminus to form either homo- or heterocollagen triple helices. (14) After secretion from the cell, the C-propeptides are enzymatically removed. Here we describe a large family with a COL2A1 mutation within the C-propeptide of type II collagen. The phenotype that results from this mutation does not easily fit into any of the existing categories of type II collagenopathies.
SUBJECTS, METHODS, AND RESULTS
Patients in the extended family were identified following independent referral of two family members to the genetics department of the University Hospital of Wales. Written consent to examination and DNA analysis was obtained in all cases as part of their clinical management. Affected subjects ranged in age from 22 to 60 years and presented with both ophthalmic and skeletal phenotypes. The vitreoretinal changes were characteristic with extensive lattice retinopathy, covering approximately two to three clock hours in each quadrant of some patients. Although the vitreous did not exhibit the congenital membraneous anomaly characteristic of Stickler syndrome type 1, (15-17) the architecture was strikingly abnormal, with absence of the usual lamellar array. Affected subjects had a spherical mean refractive error of -1.46 dioptres (SD 1.5), which was not significantly greater than that in unaffected subjects (mean refractive error -0.71, SD 0.99, p=0.13, Mann-Whitney test). The axial length was slightly greater in affected eyes (mean 24.6 mm, SD 0.73) compared with unaffected eyes (mean 23.8 mm, SD 1.1, p=0.008, t test). A single affected subject, whose axial length had increased to 33.5 mm, following retinal detachment surgery, distorted any apparent variation in myopia between affected and unaffected subjects and is not included in the analysis of ammetropia or axial lengths. In one case (III.8) bilateral retinal detachment occurred at 13 years of age resulting in …