Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2

Abstract

The inherited osteolysis syndromes are a heterogeneous group of skeletal disorders whose classification is still uncertain. Three osteolysis syndromes show autosomal recessive inheritance and multicentric involvement: Torg syndrome (OMIM 259600), Winchester syndrome (OMIM 277950) and Nodulosis-Arthropathy-Osteolysis syndrome (NAO; OMIM 605156). The 2001 Nosology of the International Skeletal Dysplasia Society (Hall CM, Am J Med Genet 2002: 113: 65) classifies NAO as a variant of Torg syndrome, while Winchester syndrome is considered as a separate disorder. Recently, mutations in the matrix metalloproteinase 2 (MMP2) gene were identified in affected individuals with a clinical diagnosis of NAO in two Arab families. We report a homozygous missense mutation (E404K) in the active site of MMP2 in a 21-year-old woman with a severe form of osteolysis best compatible with a diagnosis of Winchester syndrome. The clinical and molecular findings suggest that Torg, NAO and Winchester syndromes are allelic disorders that form a clinical spectrum.

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

“…MMP20 deficiency from homozygous recessive mutation in the zinc catalytic site renders the enzyme inactive and results in hypomaturation amelogenesis imperfecta (205). The Italian patient with MMP2 mutation also had discolored and easily chipped teeth, possibly due to altered MMP20 (315). The only apparent disturbances in these patients was with bone structures; however, it would be interesting to know of their immune system function or the presence of any lung dysfunction.…”

“…The afflicted family members have no detectable MMP2, resulting from a missense mutation in the MMP2 allele (162). Recently, another osteolytic disorder, Winchester syndrome, is also linked to a homozygous recessive mutation in the MMP2 active site found in a patient in Southern Italy who has generalized osteoporosis and severe osteolytic changes, including brachydactyly of the hands and feet (315). It has also been hypothesized that Torg syndrome, a less severe osteolytic disease, may also be related to MMP2 mutations; however, this has not been tested.…”

Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development

“…Humans with recessive mutations in MMP2 have flattened faces (Al Aqeel et al, 2000;AlMayouf et al, 2000;Zankl et al, 2005). The facial features were also changed in the Mmp2 -/-;Col1a1 r/r mice, which had shortened snouts and bulging skulls ( Fig.…”

“…Humans null for MMP2 have severe osteolytic syndromes, whereas Mmp2 -/-mice have only mild skeletal defects (Itoh et al, 1997;Al Aqeel et al, 2000;Al-Mayouf et al, 2000;Martignetti et al, 2001;Zankl et al, 2005;Inoue et al, 2006;Rouzier et al, 2006). The spontaneous occurrence of a low penetrance, runted phenotype with abnormal craniofacial features in our Mmp2 -/-mouse colony led us to hypothesize that there were genetic modifiers of Mmp2.…”

“…Inactivating mutations in human MMP2 are the cause of rare but severe skeletal defect syndromes in patients born from consanguineous marriages (Martignetti et al, 2001;Zankl et al, 2005;Rouzier et al, 2006). The clinical findings in these MMP2-null patients include hyperextension of metacarpophalangeal joints, flexion contractures of large joints, dysmorphic faces, significant growth restrictions and, surprisingly, loss of bone mass with osteolysis (Al Aqeel et al, 2000;Al-Mayouf et al, 2000;Zankl et al, 2005;Rouzier et al, 2006).…”