MMP2 – Multicentric Osteolysis-Nodulosis-Arthropathy Spectrum

Autosomal recessive mutations in the matrix metalloproteinase 2 gene (MMP2) underlie the multicentric osteolysis-nodulosis-arthropathy spectrum (MONDO:0018298). Affected individuals present with progressive osteolysis of carpal, tarsal and interphalangeal joints, subcutaneous nodules, arthropathy and variable extraskeletal features such as hirsutism (HP:0001007) and corneal opacity (HP:0007957).

To date, over 44 individuals carrying 22 distinct MMP2 variants have been reported worldwide, including missense, frameshift and splice-site mutations clustered in the catalytic and gelatin-binding domains ([PMID:31268248]). The variant spectrum spans homozygous and compound heterozygous alleles, with recurrent exon-8 changes such as c.1188C>A (p.Ser396Arg) and c.1228G>C (p.Gly410Arg).

Segregation analysis across at least five unrelated families confirms autosomal recessive inheritance, with ten additional affected sibs segregating biallelic MMP2 alleles in consanguineous pedigrees ([PMID:16542393]). Carrier parents and unaffected heterozygotes are phenotypically normal, supporting complete loss-of-function as the pathogenic mechanism.

Functional studies demonstrate that catalytic-domain mutations abolish gelatinase activity. Gelatin zymography of patient-derived mutants (e.g., p.Gly410Arg) shows complete loss of MMP2 processing in cell assays ([PMID:25273674]), and Mmp2–/– mice recapitulate key skeletal and cytokine dysregulation features seen in patients ([PMID:33101055]). Earlier domain-mapping via mutagenesis of the type-II module confirms that selected residues are critical for substrate binding and structural integrity ([PMID:9914534]).

Collectively, this evidence fulfills ClinGen criteria for a Definitive gene–disease association, with strong genetic segregation and concordant experimental models. MMP2 mutation screening should be integrated into diagnostic panels for pediatric osteolysis syndromes, enabling early molecular diagnosis and prognostic stratification.

Key Take-home: Biallelic MMP2 loss-of-function mutations cause multicentric osteolysis-nodulosis-arthropathy spectrum via impaired gelatinase activity, with robust genetic and functional validation underpinning clinical testing utility.

References

• Molecular Genetics & Genomic Medicine | 2019 | A novel mutation in the matrix metallopeptidase 2 coding gene associated with intrafamilial variability of multicentric osteolysis, nodulosis, and arthropathy. [PMID:31268248]
• Clinical Genetics | 2006 | A novel homozygous MMP2 mutation in a family with Winchester syndrome. [PMID:16542393]
• Journal of Human Genetics | 2014 | Functional characterisation of a novel mutation affecting the catalytic domain of MMP2 in siblings with multicentric osteolysis, nodulosis and arthropathy. [PMID:25273674]
• Frontiers in Physiology | 2020 | Comparative Serum Analyses Identify Cytokines and Hormones Commonly Dysregulated as Well as Implicated in Promoting Osteolysis in MMP-2-Deficient Mice and Children. [PMID:33101055]
• European Journal of Biochemistry | 1999 | The gelatin-binding site of the second type-II domain of gelatinase A/MMP-2. [PMID:9914534]

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