Molecular Genetic Study of Avascular Necrosis of the Femoral Head

Avascular necrosis of the femoral head (ANFH) is a debilitating disease that usually leads to destruction of the hip joint in the third to fifth decade of life (average age, 36 years). The disease prevalence is unknown, but it has been estimated that 10,000-20,000 new cases per year are diagnosed in the United State. Nearly half of the patients eventually require hip replacement before 40 years of age. The etiology of ANFH is unknown but previous studies indicated that heritable thrombophilia (increased tendency to form thrombi) and hypofibrinolysis (reduced ability to lyse thrombi), alcohol intake, and steroid use are risk factors for ANFH.

Although the majority of idiopathic ANFH cases are sporadic, recently we identified three ANFH families showing autosomal dominant inheritance. By genome-wide scan, a significant two-point LOD score of 3.45 at = 0 was obtained between one ANFH pedigree and marker D12S85 on chromosome 12. High-resolution mapping was conducted in a second ANFH family and replicated the linkage to D12S368. When an age-dependent penetrance model was applied, the combined multipoint LOD score achieved 6.43 between D12S1663 and D12S85. Furthermore, by using haplotype analysis and gene-based mutation detection, we have identified the collagen type II, alpha 1 (COL2A1) gene, as the ANFH disease gene. Re-sequencing of the type II collagen (COL2A1) gene demonstrated a glycine with serine mutation in the G-X-Y repeat of type II collagen, in all affected individuals in three pedigrees. In the Pedigree I, a 3665G >A mutation in exon 50 of the COL2A1 gene (Genbank accession number NM_001844) and the substitution resulted in a Gly1170Ser codon change (Genbank accession number NP_001835). A second pedigree was shown to harbor the same mutation but the mutant allele existed in a different haplotype background. In a third pedigree, a 2306G>A mutation occurred in exon 33 of the gene (Genbank accession number NM_001844), causing glycine to serine change at codon 717 (Genbank accession number NP_001835).

On this basis, we propose to study the pathophysiological mechanism(s) of inherited and sporadic ANFH. The main focus of this project includes: (1) Establishing cell line and animal models to investigate the molecular basis of ANFH pathogenesis. (2) Conducting genetic analysis on sporadic ANFH cases, including those who are idiopathic, alcohol consumers or steroid-induced. (3) Using COL2A1 gene as a target, we will design novel therapeutics and prediction procedures to improve the management of the ANFH patients.