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Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome
J A Martignetti1, A A Aqeel, W A Sewairi
1Department of Human Genetics, Mount Sinai School of Medicine, Box 1498, Fifth Avenue at 100th Street, New York, New York, USA. john.martignetti@mssm.edu
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.
Insights
Rare vanishing bone diseases involve bone destruction. Genetic analysis identified mutations in the MMP2 gene, leading to a lack of enzyme activity and causing multicentric osteolysis in Saudi Arabian families.
Area of Science:
- Genetics
- Molecular Biology
- Rheumatology
Background:
- Inherited osteolyses, or vanishing bone syndromes, are rare disorders characterized by bone destruction and resorption.
- Multicentric osteolyses present with interphalangeal joint erosions, mimicking severe juvenile rheumatoid arthritis.
Purpose of the Study:
- To identify the genetic cause of an autosomal recessive form of multicentric osteolysis observed in Saudi Arabian families.
- To investigate the role of the MMP2 gene in this specific osteolysis syndrome.
Main Methods:
- Genome-wide search for homozygous-by-descent microsatellite markers in affected families.
- Haplotype analysis to narrow down the critical genetic region.
- Mutation analysis and molecular modeling of the MMP2 gene and its protein product.
Main Results:
- The disease gene was localized to chromosome 16q12-21, specifically within a 1.2-cM region containing the MMP2 gene.
- Two family-specific homoallelic mutations (R101H and Y244X) in the MMP2 gene were identified.
- Affected individuals showed no detectable MMP2 enzymatic activity in serum or fibroblasts.
Conclusions:
- Mutations in the MMP2 gene are causative of this autosomal recessive multicentric osteolysis syndrome.
- The identified mutations disrupt MMP2 function, leading to bone resorption and associated clinical features.
- This finding expands the understanding of vanishing bone diseases and the role of MMP2 in skeletal integrity.
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