Age at onset-dependent presentations of premature hip osteoarthritis, avascular necrosis of the femoral head, or Legg-Calvé-Perthes disease in a single family, consequent upon a p.Gly1170Ser mutation of COL2A1.
OBJECTIVE
To identify the genetic abnormality responsible for osteoarthritis (OA), avascular necrosis (AVN) of the femoral head, and Legg-Calvé-Perthes disease in a single family, and to determine factors responsible for the distinct phenotypes manifested by different family members.


METHODS
Forty-two members of a 5-generation family were recruited and investigated. Diagnosis was made by independent orthopedic surgeons and radiologists. Histopathologic changes of the diseased tissue were examined. Linkage analysis was performed with markers spanning the COL2A1 locus. Haplotypes were constructed and mutation of the gene was detected. Structures of the wild-type and mutant proteins were modeled.


RESULTS
Sixteen affected members were identified (5 with isolated precocious hip OA, 6 with AVN of the femoral head, and 5 with Legg-Calvé-Perthes disease). A p.Gly1170Ser mutation of COL2A1 cosegregated with the 3 diseases and was absent in controls. Of note, age at onset in relation to the closure status of the femoral head epiphysis was associated with the diseases, with Legg-Calvé-Perthes disease presenting prior to closure (at ages 6-14 years), AVN of the femoral head presenting during closure (at ages 15-18 years), and precocious OA of the hip presenting after closure (at ages 21-34 years). Molecular modeling predicted that the serine-to-glycine substitution loosens the helical structure of the protein.


CONCLUSIONS
The p.Gly1170Ser mutation of COL2A1 in the family described is responsible for pathology confined to the hip joint, which presents as isolated precocious hip OA, AVN of the femoral head, or Legg-Calvé-Perthes disease. Age at onset in relation to closure of the femoral head epiphysis appears to be a critical factor in determining disease pattern.
Second Affiliated Hospital and Center for Genome Research, Sun Yat-Sen University, Guangzhou, China.
Peiqiang
P
Su
Ru
R
Li
Shangli
S
Liu
Yan
Y
Zhou
Xinguang
X
Wang
Nilesh
N
Patil
Christopher S
CS
Mow
Justin C
JC
Mason
Dongsheng
D
Huang
Yiming
Y
Wang
D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D024043:Collagen Type II / Q000235:genetics*; D004838:Epiphyses / Q000254:growth & development / Q000503:physiopathology; D005260:Female; D005271:Femur Head Necrosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007873:Legg-Calve-Perthes Disease / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
C499177:COL2A1 protein, human; D024043:Collagen Type II