Type II collagen gene variants and inherited osteonecrosis of the femoral head.
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 G-->A 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 G-->A 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.
Liu
Yu-Fen
YF
Institute of Genetics and Genome Research Center, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Chen
Wei-Ming
WM
Lin
Yung-Feng
YF
Yang
Ruei-Cheng
RC
Lin
Ming-Wei
MW
Li
Ling-Hui
LH
Chang
Ya-Hui
YH
Jou
Yuh-Shan
YS
Lin
Pei-Yu
PY
Su
Jih-Shyun
JS
Huang
Shiu-Feng
SF
Hsiao
Kwang-Jen
KJ
Fann
Cathy S J
CS
Hwang
Hun-Way
HW
Chen
Yuan-Tsong
YT
Tsai
Shih-Feng
SF
D000328:Adult; D002648:Child; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D024043:Collagen Type II / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005271:Femur Head Necrosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011859:Radiography; D017422:Sequence Analysis, DNA
C499177:COL2A1 protein, human; D024043:Collagen Type II