title: Functional characterisation of a novel mutation affecting the catalytic domain of MMP2 in siblings with multicentric osteolysis, nodulosis and arthropathy.
abstract: Multicentric osteolysis, nodulosis and arthropathy (MONA) is a rare autosomal recessive disorder. To date, 13 mutations of the matrix metalloproteinase 2 (MMP2) gene have been detected in 26 patients with MONA and other osteolytic syndromes. Here, we describe the molecular and functional analysis of a novel MMP2 mutation in two adult Italian siblings with MONA. Both siblings displayed palmar-plantar subcutaneous nodules, tendon retractions, limb arthropathies, osteolysis in the toes and pigmented fibrous skin lesions. Molecular analysis identified a homozygous MMP2 missense mutation in exon 8 c.1228G>C (p.G410R), not detected in 260 controls and predicted by several bioinformatic tools to be pathogenic. By protein modelling, the mutant residue was predicted to affect the main chain conformation of the catalytic domain. Gelatin zymography, the gold standard test for MMP2 function, of serum-free conditioned medium from G410R-MMP2-expressing human embryonic kidney (HEK) cells, showed a complete loss of gelatinolytic activity. The novel mutation is located in the catalytic domain, as are 3 (p.E404K, p.V400del and p.G406D) of the other 13 MMP2 mutations described to date; however, p.G410R underlies a phenotype that is only partially overlapping that of other MMP2 exon 8 mutation carriers. Our results further delineate the complexity of genotype-phenotype correlations in MONA, broaden the repertoire of reported MMP2 mutation and enhance the comprehension of the protein motifs crucial for MMP2 catalytic activity.
authors.affiliation: Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Azzollini
authors.affiliation: Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rovina
authors.affiliation: Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasini
authors.affiliation: Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Parenti
authors.affiliation: Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fratoni
authors.affiliation: Department of Biology, University 'Federico II', Naples, Italy.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Cubellis
authors.affiliation: Dermatologic Unit, Department of Health Sciences, San Paolo Hospital, University of Milan, Milan, Italy.
authors.forename: Amilcare
authors.initials: A
authors.lastname: Cerri
authors.affiliation: Operative Unit of Orthopaedics and Traumatology, Department of Health Sciences, San Paolo Hospital, University of Milan, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pietrogrande
authors.affiliation: 1] Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy [2] Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D020134:Catalytic Domain / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010014:Osteolysis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D035781:Siblings
chemical_list: C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2