MMP2 and the Multicentric Osteolysis, Nodulosis, and Arthropathy (MONA) and Winchester Syndromes

Abstract The inherited osteolyses or “vanishing bone” syndromes are a group of rare skeletal disorders (Torg and Steel, 1968; Torg et al., 1969; Whyte et al., 1978; Fryns et al., 1980; Hemingway et al., 1983; Hardegger et al., 1985; Petit and Fryns, 1986; Raat et al., 1994; Brennan and Pauli, 2001) distinguished by their differing anatomical distribution, degrees of severity, inheritance pattern, and associated syndromic features (Hardegger et al., 1985; Petit and Fryns, 1986). Multicentric osteolysis with nodulosis and arthropathy [MONA, NAO, or Al Aqeel–Sewairi, syndrome (OMIM 605156)] is an autosomal recessive member of this group notable for the extent of carpal and tarsal osteolysis and interphalangeal joint erosions, facial dysmorphia, and the presence of 2brocollagenous nodules (Al Aqeel et al., 2000). The availability of three large and unrelated families with this syndrome originally permitted a positional cloning approach to identifythecausative gene. Agenome-wide search was performed for regions that were homozygous by descent and the disease gene was localized to 16q12-21. Molecular analysis of the candidate genes within this locus found that all MONA affected patients lacked MMP2 gelatinolytic activity and that this de2ciency was the result of inactivating mutations in the MMP2 gene (Martignetti et al., 2001). Since this original report, a number of additional individuals with vanishing bone disease and MMP2 mutations have been identi2ed, revealing the pan-ethnic nature of the disease. Most recently, novel findings suggest that Winchester syndrome (Zankl et al., 2005; Rouzier et al., 2006) and MONA may be allelic variants representing a spectrum of MMP2 deficiency disorders.