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

Pallos, D.; Hart, P.S.; Cortelli, J.R.; Vian, S.; Wright, J.T.; Korkko, J.; Brunoni, D.; Hart, T.C.

« Previous Next »Archives of Oral Biology
Volume 46, Issue 5 , Pages 459-470, May 2001

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

D. Pallos
- Department of Periodontology, School of Dentistry, University of Taubate, Sao Paulo, SP Brazil
P.S. Hart
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
J.R. Cortelli
- Department of Periodontology, School of Dentistry, University of Taubate, Sao Paulo, SP Brazil
S. Vian
- Department of Periodontics, School of Dentistry, Faculdade Integradas Maria Coelho Aguiar, Porto Velho RO, Brazil
J.T. Wright
- Department of Pediatric Dentistry, University of North Carolina, Chapel Hill, NC, USA
J. Korkko
- Center for Gene Therapy, MCP Hahnemann University, Philadelphia, PA, USA
D. Brunoni
- Centro de Genetica Medica, UNIFESP; Sao Paulo, Brazil
T.C. Hart
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Corresponding author. Tel.: +1-412-3837695; fax: +1-412-6243080

Accepted 22 September 2000.

Abstract

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 concerned about discoloration of her teeth, found to be 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, θ=0.00). All DGI-affected family members shared a common haplotype, which was not present in individuals without DGI. Haplotype analysis sublocalized the gene to a 5-cM genetic interval that contained the collagen 1α1 (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 five mutations, mutational analysis was performed on the remaining exons including intron–exon boundaries, which resulted in identification of a Gly559Cys mutation in exon 32, present in all DGI-affected family members. Clinical features segregating with this G559C mutation included hyperextensible joints, joint pain and an increased propensity for bone fractures with moderate trauma. This is the first report of joint pain associated with a COL1A1 mutation and DGI. The mild skeletal features and reduced penetrance of the non-dental findings illustrate the importance of genetic evaluations for families with a history of DGI.

Keywords: Dentinogenesis imperfecta, Joint pain, Joint hyperflexibility, Chromosome 17q21, Collagen 1A1, Osteogenesis imperfecta

Abbreviations: COL1A1, collagen 1 alpha 1, COL1A2, collagen 1 alpha 2, DLX-3 distal less-3, EDS, Ehlers–Danlos syndrome, LOD, logarithm of the odds, MIM, Mendelian inheritance in man, PAGE, polyacrylamide gel electrophoresis, PCR, polymerase chain reaction, STRP, short tandem repeat polymorphism