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Previous Volume 352:2294-2301 June 2, 2005 Number 22 Next

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ABSTRACT

Background Avascular necrosis of the femoral head (ANFH) causes disability that often requires surgical intervention. Most cases of ANFH are sporadic, but we identified three families in which there was autosomal dominant inheritance of the disease and mapped the chromosomal position of the gene to 12q13.

Methods We carried out haplotype analysis in the families, selected candidate genes from the critical interval for ANFH on 12q13, and sequenced the promoter and exonic regions of the type II collagen gene (COL2A1) from persons with inherited and sporadic forms of ANFH.

Results We identified a GA transition in exon 50 of COL2A1 in affected members of a four-generation family with ANFH. This transition predicts the replacement of glycine with serine at codon 1170 in a GXY repeat of type II collagen. Another pedigree was shown to harbor the same transition, but the mutant allele occurred on a different haplotype background. In a third family, a GA transition in exon 33 of the gene, causing a glycine-to-serine change at codon 717, was detected. No mutation was found in the COL2A1 coding region in sporadic cases of ANFH.

Conclusions All the patients with familial ANFH whom we studied carried COL2A1 mutations. In families with ANFH, haplotype and sequence analysis of the COL2A1 gene can be used to identify carriers of the mutant allele before the onset of clinical symptoms, allowing the initiation of measures that may delay progression of the disease.

Source Information

From the Institute of Genetics and Genome Research Center (Y.-F. Liu, J.-S.S., K.-J.H., S.-F.T.) and the Department of Surgery (W.-M.C., P.-Y.L.) and Faculty of Medicine (M.-W.L.), School of Medicine, National Yang-Ming University; the Departments of Orthopedics and Traumatology (W.-M.C.), Medical Research and Education (M.-W.L., K.-J.H.), and Ophthalmology (P.-Y.L.), Taipei Veterans General Hospital; the Division of Molecular and Genomic Medicine, National Health Research Institutes (Y.-F. Lin, L.-H.L., Y.-H.C., Y.-S.J., S.-F.H., S.-F.T.); the Division of Orthopedics and Traumatology, Taipei Municipal Chung-Hsing Hospital (R.-C.Y.); the Department of Pathology, Chang Gung Memorial Hospital (S.-F.H.); and the Institute of Biomedical Sciences, Academia Sinica (C.S.J.F., H.-W.H., Y.-T.C.) — all in Taipei, Taiwan.

Drs. Liu and W.-M. Chen contributed equally to this work.

Address reprint requests to Dr. Tsai at the Division of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, or at petsai{at}nhri.org.tw.

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