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

Nature Genetics volume 28, pages 261–265 (2001)Cite this article

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 families1,2. 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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Figure 1: Pedigrees and haplotypes of the Saudi kindreds.
Figure 2: a, Gelatin zymography of control and affected serum samples.
Figure 3: a, Molecular representation of wildtype human MMP2.

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Acknowledgements

We thank the families who participated in these studies; M. Palmer, K. Quadrini, P. Prabhudass, R. Kahn, and K. Brown for technical assistance; and I. Visiers for discussions. This work was supported in part by grants from the National Institutes of Health, including a merit award (5 R37 DK34045), research grants (5 R01 DK26824 and R01 NS39893), a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center, and a grant (5 P30 HD28822) for the Mount Sinai Child Health Research Center.

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Authors and Affiliations

  1. Department of Human Genetics, Mount Sinai School of Medicine, Box 1498, Fifth Avenue at 100th Street, New York, New York, USA

    John A. Martignetti, Oonagh Dowling, Juliette Harris & Robert J. Desnick

  2. Department of Pediatrics, Mount Sinai School of Medicine, Box 1498, Fifth Avenue at 100th Street, New York, New York, USA

    John A. Martignetti & Robert J. Desnick

  3. Riyadh Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia

    Aida Al Aqeel & Wafaa Al Sewairi

  4. King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia

    Aida Al Aqeel, Christine E. Boumah, Marios Kambouris, S. Al Mayouf, K.V. Sheth, W. Al Eid, Sultan Bahabri & Brian F. Meyer

  5. Yale University School of Medicine, New Haven, Connecticut, USA

    Marios Kambouris

  6. Department of Neurobiology (Structural Neurobiology and Proteomics Laboratory), Mount Sinai School of Medicine, Box 1498, Fifth Avenue at 100th Street, New York, New York, USA

    Marc J. Glucksman

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  1. John A. Martignetti
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Correspondence to John A. Martignetti.

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Martignetti, J., Aqeel, A., Sewairi, W. et al. Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet 28, 261–265 (2001). https://doi.org/10.1038/90100

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