4 Med Genet 1993; 30: 492-496 Osteogenesis imperfecta type III: mutations in the type I collagen structural genes, COLlAl and COL1A2, are not necessarily responsible Gillian A Wallis, Bryan Sykes, Peter H Byers, Christopher G Mathew, Denis Viljoen, Peter Beighton Department of Biochemistry and Molecular Biology, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. G A Wallis University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. B Sykes Division of Medical and Molecular Genetics, Paediatric Research Unit, Guy's Hospital, London SEI 9RT, UK. C G Mathew Department of Pathology, University of Washington, Seattle, WA 98195, USA. P H Byers Department of Human Genetics, Medical School, University of Cape Town, Observatory 7925, South Africa. P Beighton D Viljoen Correspondence to Dr Wallis. Received 12 November 1992. Revised version accepted 16 December 1992. Abstract Most forms of osteogenesis imperfecta are caused by dominant mutations in either of the two genes, COLlAl and COL1A2, that encode the prooal(I) and proa2(I) chains of type I collagen, re- spectively. However, a severe, autosomal recessive form of OI type III with a comparatively high frequency has been recognised in the black populations of southern Africa. We performed linkage analyses in eight OI type III families using RFLPs associated with the COLIAl and COLIA2 loci to determine whether mutations in the genes for type I collagen were responsible for this form of OI. Recombination between the OI pheno- type and polymorphic markers at both loci was shown in three of the eight fam- ilies investigated. The combined lod scores for the eight families were - 10O6 for COLlAl and -11P2 for COL1A2. Further, we examined the type I procol- lagen produced by skin fibroblast cul- tures derived from 15 affected and 12 unaffected subjects from the above eight families plus one further family. We found no evidence for defects in the synthesis, structure, secretion, or post- translational modification of the chains of type I procollagen produced by any of the family members. These results suggest that mutations within or near the type I collagen structural genes are not responsible for this form of OI. (J7 Med Genet 1993;30:492-6) Osteogenesis imperfecta (OI) is currently sub- classified into four major groups and several subtypes on the basis of clinical and genealogi- cal data.'2 According to the original classifica- tion by Sillence et al,' 01 type III is character- ised by a severe propensity to fracturing, marked short stature, progressive deformities, and white sclerae and, as the phenotype oc- curred sporadically, new dominant mutation or autosomal recessive inheritance was postu- lated. Subsequently, Sillence et aP identified seven families in a review of 345 pedigrees of different types of OI where the OI type III phenotype appeared to have an autosomal re- cessive mode of transmission. There is now accumulating evidence that the OI type III phenotype most often results from dominant mutations in either of the two genes that encode the proal(I) and proa2(I) chains (COLlAl and COL1A2, respectively) of type I collagen.4-" In only one instance has a defect in the genes for type I collagen been shown to cause a recessive form of OI type IIJ.11124 In a further family postulated to have a recessive form of OI type III, linkage studies have excluded the involvement of the type I colla- gen genes.'5 In contrast to world wide figures, an autoso- mal recessive (AR) form of OI type III is comparatively common in the black popula- tion of southern Africa, where more than 70 affected persons have been studied.'""5 In general, recessive inheritance of this condition has been inferred on the basis of recurrence of the defined phenotype in sibs born to unaffec- ted parents and the frequency of the pheno- type. We performed linkage analysis and ex- amined collagen synthesis and secretion in skin fibroblast cultures to determine whether muta- tions in the genes for type I collagen were responsible for this form of OI in southern African patients. Patients and methods PATIENTS The patients and relatives who participated in this study had been examined previously and were derived from reported series of affected persons in southern Africa.1'-9 On the basis of genealogical, phenotypic, and radiological cri- teria the affected subjects were classified as having an AR form of OI type III. The pedi- grees are shown in the figure. Apart from family 1 who were of mixed ancestry (African Negro origin with Scottish and Indian admix- ture),'9 all the participants were from the black populations of southern Africa. All affected subjects had severe dwarfism, multiple frac- tures, and marked skeletal deformity owing to bone malleability. The sclerae were white, or in younger children had a slight blue tinge, and dentinogenesis imperfecta was variable. Con- siderable intrafamilial variability of these latter features was recognised and so they were not considered to be indicative of syndromic heterogeneity.'8 Families 1 to 7 were selected for study as there was more than one affected subject born to normal parents. Families 8 and 9 were included in the study as, although the condition occurred sporadically in these fami- lies, the phenotype of the affected subjects was indistinguishable from the familial condition. In all instances, the parents of affected subjects were normal. 492 on May 29, 2020 by guest. Protected by copyright. http://jmg.bmj.com/ J Med Genet: first published as 10.1136/jmg.30.6.492 on 1 June 1993. Downloaded from