Novel MMP20 (matrix metalloproteinase 20) mutations causing hypoplastic-hypomaturation amelogenesis imperfecta

Matrix metalloproteinase 20 (MMP20) is a proteinase essential for dental enamel formation. Mutations in human MMP20 cause autosomal recessive amelogenesis imperfecta (AI), characterized by thin and soft enamel. This study aimed to unravel the genetic causes for five families with hypoplastic-hypomaturation AI.

Whole-exome analyses and Sanger sequencing were performed to identify and confirm disease-causing mutations. To evaluate the pathogenicity of identified MMP20 missense variants, immunoblotting and gelatin zymography were conducted on proteins overexpressed in HEK293T cells.

All affected individuals from the five families exhibited similar dental phenotypes, including chalky-white to yellow-brown discolorations and evident dental attrition. The defective enamel was both thin and hypomineralized. Six pathogenic MMP20 variants were identified: c.289A>T (p.Lys97∗), c.547G>A (p.Asp183Asn), c.686G>A (p.Gly229Asp), c.102G>A (p.Trp34∗), c.359dup (p.Asn120Lysfs∗9), and c.954-2A>T. Among them, the first three have not been previously reported. The two missense mutations altered evolutionarily conserved amino acid residues within the catalytic domain of MMP20. Compared with the wild type, secretion of both mutant MMP20 proteins was significantly impeded, and neither displayed proteolytic activity on gelatin zymography, indicating a loss of enzymatic function.

This study expands the genotypic spectrum of MMP20-associated AI and highlights two critical residues within the MMP20 catalytic domain that are essential for its secretion and enzymatic activity.