A novel mutation in the matrix metallopeptidase 2 coding gene associated with intrafamilial variability of multicentric osteolysis, nodulosis, and arthropathy

Abstract

Background MONA, which stands for a spectrum of Multicentric Osteolysis, subcutaneous Nodulosis, and Athropathia, is an ultra rare autosomal recessive disorder caused by mutations in the matrix metallopeptidase 2 (MMP2) gene. To date only 44 individuals, carrying 22 different mutations have been reported. Here we report on two brothers with identical homozygous MMP2 gene mutations, but with clearly different phenotypes. Methods Genomic DNA was isolated from the affected brothers and the parents. An iliac crest bone biopsy was taken from the younger patient (index case). The level of matrix metallopeptidase 2 enzyme (MMP2) in serum and synovial fluid of the younger patient was analyzed using gelatin zymography. Results The DNA analysis revealed a homozygous c.1188C>A transversion on exon 8 of the gene. The affected brothers had the same homozygous variant and the parents were heterozygous to this variant. This variant has been reported as a compound heterozygous mutation on one individual resulting in scleroderma like skin thickening. Bone histomorphometry indicated increased trabecular bone remodeling and turnover. The zymography revealed that the level of MMP2 was completely nonmeasurable in the serum and only a minor gelatinolytic protein band of about similar molecular weight as MMP2 was found in the synovial fluid. Conclusions Both the age at the onset and the phenotypic severity of the syndrome in these two brothers were different despite identical genotypes. The younger patients had corneal opacities leading to deteriorating visual acuity. For the first time in this disease, opacities were successfully treated with corneal transplantations.

Multicentric Osteolysis, Nodulosis, and Arthropathy in Two Unrelated Children with Matrix Metalloproteinase 2 Variants: Genetic-Skeletal Correlations

“…A similar pattern usually occurs in the feet (2,3,5,(8)(9)(10)(11)(12). Non-skeletal manifestations include facial dysmorphism and oral (2,3,11,13,14,15), dermatologic (2,9,12,(14)(15)(16), ophthalmological and cardiac manifestations (2,3,7,11,13,15,17,18).…”

“…MONA syndrome is inherited through an autosomal recessive manner. It is believed that only 46 patients with 24 different variants in MMP2 are published (3,7). And that only four patients with two variants in MMP14 have been reported (2).…”

Different roles of matrix metalloproteinase 2 in osteolysis of skeletal dysplasia and bone metastasis (Review)

“…As an extremely rare genetic disease with only 46 cases and 23 mutations from 28 families reported in the literature, no exact epidemiological statistics of MONA, have been described ( 34 ). Typical clinical manifestations of MONA consist of extensive osteopenia and osteolysis (most prominent in carpal and tarsal bones), progressive osteoarthropathy, and subcutaneous nodules on the palms and soles ( 35 ).…”

“…Vanatka et al ( 37 ) reported a case of MONA with long-term follow-up, in which the pathological changes of the bones over a 23-year period were striking and the pattern of bone loss was progressive and periarticular. Furthermore, ~75% of mutations from the reported MONA cases occur in the catalytic domain or have detrimental effects on its catalytic function, resulting in impaired MMP2 activity ( 34 , 38 ). Consequently, although individual differences in clinical manifestations exist among MONA patients, almost all of them contain signs of bone loss and osteolysis, indicating that loss of MMP2 accounts for impaired bone integrity and mineral homeostasis during skeletal growth and development.…”

MMP14 in Sarcoma: A Regulator of Tumor Microenvironment Communication in Connective Tissues

“…This phenotype has been attributed largely to the importance of MMP14 in collagen turnover and bone remodeling [14,15]. While mice deficient in MMP2 exhibit relatively mild skeletal defects which result in reduced bone mineralization and joint erosion, mutations in human MMP2 and MMP14 cause the severe connective tissue syndromes known as MONA (Multicentric Osteolysis, subcutaneous Nodulosis, and Athropathia) and Winchester Syndrome, respectively [16,17,18,19].…”