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Homozygosity for a splice site mutation of the COL1A2gene yields a non-functional proα2(I) chain and an EDS/OI clinical phenotype
  2. D VALLER*§,
  3. S WALLIS,
  4. F M POPE
  1. *MRC Connective Tissue Genetics Group, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
  2. †Dingley Child Development Centre, Battle Hospital, Oxford Road, Reading, Berks RG3 1AG, UK
  3. ‡Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF4 4XN, UK
  1. Dr Nicholls, alan{at}

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Editor—Type I collagen is the major structural protein of skin, bone, tendon, ligaments, and cornea. It is a heterotrimer of two α1(I) chains and one α2(I) chain. Mutations in one of its two structural genes (COL1A1,COL1A2) underlie the inherited disorders osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome types VIIA and B (EDS VIIA, EDS VIIB).1 Mutations which inhibit the processing of the protein precursor, procollagen, cause the ligamentous laxity and extreme joint hypermobility of EDS VII. Structural abnormalities and/or reduced production of type I collagen lead to the increased bone fragility, thin skin, blue sclerae, dentinogenesis imperfecta, and presenile deafness of osteogenesis imperfecta. The OI phenotype can vary from perinatally lethal to mild disease depending upon the nature of the mutation. Among the mild group are patients who are heterozygous for a non-functional COL1A1allele.2-5 Homozygosity for a non-functionalCOL1A1 allele appears to be incompatible with life.6 Several years ago we described a male infant who was totally deficient in α2(I)chains owing to homozygosity for a non-functional COL1A2allele.7-9 He had the severe, progressively deforming type of osteogenesis imperfecta (OI type III). His heterozygous third cousin parents, however, showed no overt clinical symptoms but were considered to be prematurely osteoporotic followingx ray examination. Subsequently, two further patients lacking proα2(I) chains from type I collagen were reported.10 11 However, their clinical phenotypes lacked any of the skeletal abnormalities of osteogenesis imperfecta but included generalised joint hypermobility, skin hyperextensibility, and scarring typical of the Ehlers-Danlos syndrome. We have now identified another patient homozygous for a mutation yielding non-functionalCOL1A2 alleles whose clinical phenotype showed generalised joint hypermobility and foot deformities reminiscent of Ehlers-Danlos syndrome associated with pale blue sclerae and a mild increase in bone fragility characteristic of osteogenesis imperfecta.

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  • § Present address: Clinical Molecular Genetics Laboratory, Addenbrooke's Hospital, Hills Road, Cambridge, UK