title: Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.
abstract: 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. 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.
authors: Department of Human Genetics, Mount Sinai School of Medicine, Box 1498, Fifth Avenue at 100th Street, New York, New York, USA. john.martignetti@mssm.edu
authors: J A
authors: JA
authors: Martignetti
authors: A A
authors: AA
authors: Aqeel
authors: W A
authors: WA
authors: Sewairi
authors: C E
authors: CE
authors: Boumah
authors: M
authors: M
authors: Kambouris
authors: S A
authors: SA
authors: Mayouf
authors: K V
authors: KV
authors: Sheth
authors: W A
authors: WA
authors: Eid
authors: O
authors: O
authors: Dowling
authors: J
authors: J
authors: Harris
authors: M J
authors: MJ
authors: Glucksman
authors: S
authors: S
authors: Bahabri
authors: B F
authors: BF
authors: Meyer
authors: R J
authors: RJ
authors: Desnick
mesh_terms: D000595:Amino Acid Sequence; D001168:Arthritis / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006801:Humans; D008126:Lod Score; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010014:Osteolysis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D012529:Saudi Arabia / Q000453:epidemiology; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
chemical_list: D020778:Matrix Metalloproteinase 2