RESUMEN
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.
Asunto(s)
Dominio Catalítico/genética , Metaloproteinasa 2 de la Matriz/genética , Mutación Missense , Osteólisis/genética , Hermanos , Adulto , Secuencia de Aminoácidos , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Células HEK293 , Homocigoto , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 2 de la Matriz/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Osteólisis/metabolismo , Osteólisis/patología , Linaje , Estructura Terciaria de Proteína , Homología de Secuencia de AminoácidoRESUMEN
In 1994, Giuffré et al. reported two unrelated families in which some of the members had microcephaly and radio-ulnar synostosis, suggesting a new condition. Since this first report, Tsukahara et al. and Udler et al. described two distinct patients with a different condition characterized by radio-ulnar synostosis, short stature, microcephaly, scoliosis, and mental retardation. Here we report on a new case of microcephaly and radio-ulnar synostosis and discuss the possible relationship between Tsukahara's syndrome and the phenotype described by Giuffré et al.