Large-scale screening for candidate genes of ossification of the posterior longitudinal ligament of the spine.
Ossification of the posterior longitudinal ligament of the spine (OPLL) is the predominant myelopathy among Japanese, and is usually diagnosed by ectopic bone formation in the paravertebral ligament in Japanese and other Asians. To detect genetic determinants associated with OPLL, we performed an extensive nonparametric linkage study with 126 affected sib-pairs using markers for various candidate genes by distinct analyses, SIBPAL and GENEHUNTER. Eighty-eight candidate genes were selected by comparing the genes identified by complementary DNA (cDNA) microarray analysis of systematic gene expression profiles during osteoblastic differentiation of human mesenchymal stem cells with the genes known to be involved in bone metabolism. Of the 24 genes regulated during osteoblastic differentiation, only one, the alpha B crystalline gene, showed evidence of linkage (p = 0.016, nonparametric linkage [NPL] score = 1.83). Of 64 genes known to be associated with bone metabolism, 7 showed weak evidence of linkage by SIBPAL analysis (p < 0.05): cadherin 13 (CDH13), bone morphogenetic protein 4 (BMP4), proteoglycan 1 (PRG1), transforming growth factor beta 3 (TGFb3), osteopontin (OPN), parathyroid hormone receptor 1 (PTHR1), and insulin-like growth factor 1 (IGF1). Among these genes, BMP4 (NPL = 2.23), CDH13 (NPL = 2.00), TGFb3 (NPL = 1.30), OPN (NPL = 1.15), and PTHR1 (NPL = 1.00) showed evidence of linkage by GENEHUNTER. Only BMP4 reached criteria of suggestive evidence of linkage. Because this gene is a well-known factor in osteogenetic function, BMP4 should be screened in further study for the polymorphism responsible.
Furushima
Kozo
K
Division of Genetic Diagnosis, The Institute of Medical Science. The University of Tokyo, Japan.
Shimo-Onoda
Kazuki
K
Maeda
Shingo
S
Nobukuni
Takahiro
T
Ikari
Katsunori
K
Koga
Hiroaki
H
Komiya
Setsuro
S
Nakajima
Toshiaki
T
Harata
Seiko
S
Inoue
Ituro
I
D000818:Animals; D001185:Artificial Intelligence; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D016022:Case-Control Studies; D003459:Crystallins / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D005820:Genetic Testing; D006801:Humans; D008297:Male; D051379:Mice; D018895:Microsatellite Repeats; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017887:Ossification of Posterior Longitudinal Ligament / Q000235:genetics*; D051381:Rats
C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D003459:Crystallins