Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome

被引:220
作者
Martignetti, JA
Al Aqeel, A
Al Sewairi, W
Boumah, CE
Kambouris, M
Al Mayouf, S
Sheth, KV
Al Eid, W
Dowling, O
Harris, J
Glucksman, MJ
Bahabri, S
Meyer, BF
Desnick, RJ
机构
[1] CUNY Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA
[2] CUNY Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA
[3] CUNY Mt Sinai Sch Med, Dept Neurobiol, Struct Neurobiol & Proteom Lab, New York, NY 10029 USA
[4] Riyadh Armed Forces Hosp, Dept Pediat, Riyadh, Saudi Arabia
[5] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Riyadh 11211, Saudi Arabia
[6] Yale Univ, Sch Med, New Haven, CT USA
关键词
D O I
10.1038/90100
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300. 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption. crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families(1,2). We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling. the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.
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页码:261 / 265
页数:5
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