Novel COL1A1 mutation (G599C) associated with mild osteogenesis imperfectaand dentinogenesis imperfecta

A genotype-phenotype analysis of a three-generation family segregating for an autosomal-dominant osteogenesis imperfecta (OI) variant is reported here , The family was ascertained through the presentation of a proband concerne d about discoloration of her teeth, found to he dentinogenesis imperfecta ( DGI). Examination of 36 family members identified 15 individuals with DGI. Linkage studies were performed for genetic markers from candidate intervals known to contain genes responsible for DGI on chromosomes 4q, 7q, and 17q. Conclusive evidence for linkage of DGI was obtained to genetic markers on chromosome 17q21-q22 (DLX-3 Z(max) = 5.34, theta = 0.00). All DGI-affected family members shared a common haplotype, which was not present in individu als without DGI. Haplotype analysis sublocalized the gene to a 5-cM genetic interval that contained the collagen 1 alpha1 (COL1A1) gene. More than 150 different COL1A1 gene mutations have been associated with various forms of OI, and five of these have been associated with DGI and type IV OI. After excluding these Eve mutations, mutational analysis was performed on the rem aining exons including intron exon boundaries, which resulted in identifica tion of a Gly559Cys mutation in exon 32, present in all DGI-affected family members. Clinical features segregating with this G559C mutation included h yperextensible joints, joint pain and an increased propensity for bone frac tures with moderate trauma. This is the first report of joint pain associat ed with a COL1A1 mutation and DGI, The mild skeletal features and reduced p enetrance of the non-dental findings illustrate the importance of genetic e valuations for families with a history of DGI, (C) 2001 Elsevier Science Lt d. All rights reserved.