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Dental malformations associated with biallelic MMP20 mutations.

ABSTRACT: BACKGROUND:Matrix metallopeptidase 20 (MMP20) is an evolutionarily conserved protease that is essential for processing enamel matrix proteins during dental enamel formation. MMP20 mutations cause human autosomal recessive pigmented hypomaturation-type amelogenesis imperfecta (AI2A2; OMIM #612529). MMP20 is expressed in both odontoblasts and ameloblasts, but its function during dentinogenesis is unclear. METHODS:We characterized 10 AI kindreds with MMP20 defects, characterized human third molars and/or Mmp20-/- mice by histology, Backscattered Scanning Electron Microscopy (bSEM), µCT, and nanohardness testing. RESULTS:We identified six novel MMP20 disease-causing mutations. Four pathogenic variants were associated with exons encoding the MMP20 hemopexin-like (PEX) domain, suggesting a necessary regulatory function. Mutant human enamel hardness was softest (13% of normal) midway between the dentinoenamel junction (DEJ) and the enamel surface. bSEM and µCT analyses of the third molars revealed reduced mineral density in both enamel and dentin. Dentin close to the DEJ showed an average hardness number 62%-69% of control. Characterization of Mmp20-/- mouse dentin revealed a significant reduction in dentin thickness and mineral density and a transient increase in predentin thickness, indicating disturbances in dentin matrix secretion and mineralization. CONCLUSION:These results expand the spectrum of MMP20 disease-causing mutations and provide the first evidence for MMP20 function during dentin formation.

SUBMITTER: Wang SK

PROVIDER: S-EPMC7434610 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Dental malformations associated with biallelic MMP20 mutations.

Wang Shih-Kai SK Zhang Hong H Chavez Michael B MB Hu Yuanyuan Y Seymen Figen F Koruyucu Mine M Kasimoglu Yelda Y Colvin Connor D CD Kolli Tamara N TN Tan Michelle H MH Wang Yin-Lin YL Lu Pei-Ying PY Kim Jung-Wook JW Foster Brian L BL Bartlett John D JD Simmer James P JP Hu Jan C-C JC

Molecular genetics & genomic medicine 20200603 8

<h4>Background</h4>Matrix metallopeptidase 20 (MMP20) is an evolutionarily conserved protease that is essential for processing enamel matrix proteins during dental enamel formation. MMP20 mutations cause human autosomal recessive pigmented hypomaturation-type amelogenesis imperfecta (AI2A2; OMIM #612529). MMP20 is expressed in both odontoblasts and ameloblasts, but its function during dentinogenesis is unclear.<h4>Methods</h4>We characterized 10 AI kindreds with MMP20 defects, characterized huma ...[more]

PMID: 32495503

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Project description:ALPL encodes tissue-nonspecific alkaline phosphatase (TNAP), an enzyme expressed in bone, teeth, liver, and kidney. ALPL loss-of-function mutations cause hypophosphatasia (HPP), an inborn error-of-metabolism that produces skeletal and dental mineralization defects. Case reports describe widely varying dental phenotypes, making it unclear how HPP comparatively affects the three unique dental mineralized tissues: enamel, dentin, and cementum. We hypothesized that HPP affected all dental mineralized tissues and aimed to establish quantitative measurements of dental tissues in a subject with HPP. The female proband was diagnosed with HPP during childhood based on reduced alkaline phosphatase activity (ALP), mild rachitic skeletal effects, and premature primary tooth loss. The diagnosis was subsequently confirmed genetically by the presence of compound heterozygous ALPL mutations (exon 5: c.346G>A, p.A116T; exon 10: c.1077C>G, p.I359M). Dental defects in 8 prematurely exfoliated primary teeth were analyzed by high resolution micro-computed tomography (micro-CT) and histology. Similarities to the Alpl-/- mouse model of HPP were identified by additional analyses of murine dentoalveolar tissues. Primary teeth from the proband exhibited substantial remaining root structure compared to healthy control teeth. Enamel and dentin densities were not adversely affected in HPP vs. control teeth. However, analysis of discrete dentin regions revealed an approximate 10% reduction in the density of outer mantle dentin of HPP vs. control teeth. All 4 incisors and the molar lacked acellular cementum by micro-CT and histology, but surprisingly, 2 of 3 prematurely exfoliated canines exhibited apparently normal acellular cementum. Based on dentin findings in the proband's teeth, we examined dentoalveolar tissues in a mouse model of HPP, revealing that the delayed initiation of mineralization in the incisor mantle dentin was associated with a broader lack of circumpulpal dentin mineralization. This study describes a quantitative approach to measure effects of HPP on dental tissues. This approach has uncovered a previously unrecognized novel mantle dentin defect in HPP, as well as a surprising and variable cementum phenotype within the teeth from the same HPP subject.

Project description:Matrix metalloproteinase 20 (MMP20) and kallikrein-related peptidase 4 (KLK4) are secreted proteinases that are essential for proper dental enamel formation. We characterized and compared enamel formed in wild-type, Mmp20 (-/-), Klk4 (-/-), Mmp20 (+/-) Klk4 (+/-), and Mmp20 (-/-) Klk4 (-/-) mice using dissecting and light microscopy, backscattered scanning electron microscopy (bSEM), SEM, microcomputed tomography (?CT), and energy-dispersive X-ray analysis (EDX). Following eruption, fractures were observed on Mmp20 (-/-), Klk4 (-/-), Mmp20 (+/-) Klk4 (+/-), and Mmp20 (-/-) Klk4 (-/-) molars. Failure of the enamel in the Mmp20 (+/-) Klk4 (+/-) molars was unexpected and suggested that digenic effects could contribute to the etiology of amelogenesis imperfecta in humans. Micro-CT analyses of hemimandibles demonstrated significantly reduced high-density enamel volume in the Mmp20 (-/-) and Klk4 (-/-) mice relative to the wild-type, which was further reduced in Mmp20 (-/-) Klk4 (-/-) mice. bSEM images of 7-week Mmp20 (-/-) and Mmp20 (-/-) Klk4 (-/-) mandibular incisors showed rough, pitted enamel surfaces with numerous indentations and protruding nodules. The Mmp20 (+/-) and Mmp20 (+/-) Klk4 (+/-) incisors showed prominent, evenly spaced, horizontal ridges that were more distinct in Mmp20 (+/-) Klk4 (+/-) incisors relative to Mmp20 (+/-) incisors due to the darkening of the valleys between the ridges. In cross sections, the Mmp20 (-/-) and Mmp20 (-/-) Klk4 (-/-) exhibited three distinct layers. The outer layer exhibited a disturbed elemental composition and an irregular enamel surface covered with nodules. The Mmp20 null enamel was apparently unable to withstand the sheer forces associated with eruption and separated from dentin during development. Cells invaded the cracks and interposed between the dentin and enamel layers. MMP20 and KLK4 serve overlapping and complementary functions to harden enamel by removing protein, but MMP20 potentially serves multiple additional functions necessary for the adherence of enamel to dentin, the release of intercellular protein stores into the enamel matrix, the retreat of ameloblasts to facilitate thickening of the enamel layer, and the timely transition of ameloblasts to maturation.

Dataset Information

Dental malformations associated with biallelic MMP20 mutations.

Publications

Dental malformations associated with biallelic MMP20 mutations.

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