A novel matrix metalloproteinase 2 (MMP2) terminal hemopexin domain mutation in a family with multicentric osteolysis with nodulosis and arthritis with cardiac defects

Abstract

Multicentric osteolysis with nodulosis and arthropathy (MONA, NAO (OMIM no. 605156)) is an autosomal recessive member of the 'vanishing bone' syndromes and is notable for the extent of carpal and tarsal osteolysis and interphalangeal joint erosions, facial dysmorphia, and the presence of fibrocollagenous nodules. This rare disorder has been described previously in Saudi Arabian and Indian families. We now report on the first Turkish family with MONA, further confirming the panethnic nature of this disease. Strikingly, and in addition to the previously noted skeletal and joint features, affected members of this family also had congenital heart defects. Molecular analysis identified a novel MMP2 inactivating mutation that deletes the terminal hemopexin domains and thus confirmed the diagnosis of MONA. On the basis of these findings, we suggest that cardiac defects may also represent a component of this syndrome and thus a physiologically relevant target of MMP-2 activity.

Figure 1

Pedigree of the Turkish family. Arrow indicates proband (patient 1, IV-2).

Figure 2

Patient 1 (IV-2) at age 6 years. (a) Note the mild hypertelorism and antimongoloid axis, strabismus, bulbous nose, large ears, small chin, and (b) gingival hypertrophy. (c) Fusiform painful swellings on all fingers and camptodactyly of the fourth finger of the left hand and the fifth finger of the right hand. (d and e) Fixed hyperextension of the halluces; palmar and plantar subcutaneous nodules are indicated by arrows.

Figure 3

Radiographs of proband (IV-2) and affected sibling. (a) Wide metacarpal bones with irregular contours especially in the fourth and the fifth fingers bilaterally. (b) Symmetric osteolytic areas in the metatarsal bones and first phalanges of the halluces. (c) Radiographs of deceased older sister (IV-1) of patient 1. Note the width of the metacarpal bones and phalanges with camptodactyly of the second and third finger of the left hand and the second finger of the right hand.

Figure 4

Patient 2 (IV-6) at age 4 years. (a) Note the bilateral mild proptosis and hypertelorism, thick lips, full cheeks, micrognathia, bulbous nose, large ears, and (b) gingival hypertrophy with high narrow palate. (c) Deformed feet with foreshortening of all toes with hyperextension of the fifth toe of the left foot and second toe of the right foot were present. (d) All fingers had painful fusiform swellings with hyperextension of the metacarpophalangeal joints and flexion contractures of the interphalangeal joints. (e) Radiographs showing carpal and metacarpal osteolysis associated with severe interphalangeal joint destruction and erosions. (f) Palmar and plantar subcutaneous nodules (indicted by arrows). (g) Radiographs showing tarsal osteolysis associated with severe interphalangeal joint destruction and erosions. (h) Note the broad medial ends of the clavicles indicated by arrowheads.

Figure 5

Frameshift mutation results in the loss of MMP-2 activity. (a) Chromatogram showing the 1732delA frameshift mutation as homozygous in the affected and heterozygous in parents of Patient. (b) Gelatin zymogram shows complete loss of MMP-2 activity in affected serum, 50% activity in that from parents, and 100% activity in noncarrier sibling and population-control serum samples. (c) Structural model of the MMP-2 mutation was based on the coordinates of the wild-type protein (PDB ID 1CK7). Yellow represents the amino portion of the molecule that is expressed before the deletion, whereas the purple C-terminal 83 amino acids are deleted in the truncation. The orange ball represents the zinc ion required for activity of the metalloprotease. Rendering was done using the program O v.12 (courtesy of Dr Alwyn Jones, University of Uppsala, Uppsala, Sweden).