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A mutation in the mouse Amelx tri-tyrosyl domain results in impaired secretion of amelogenin and phenocopies human X-linked amelogenesis imperfecta.
Barron, Martin J; Brookes, Steven J; Kirkham, Jennifer; Shore, Roger C; Hunt, Charlotte; Mironov, Aleksandr; Kingswell, Nicola J; Maycock, Joanne; Shuttleworth, C Adrian; Dixon, Michael J.
Afiliação
  • Barron MJ; Faculty of Life Sciences and School of Dentistry, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
Hum Mol Genet ; 19(7): 1230-47, 2010 Apr 01.
Article em En | MEDLINE | ID: mdl-20067920
Amelogenesis imperfecta (AI) describes a broad group of clinically and genetically heterogeneous inherited defects of dental enamel bio-mineralization. Despite identification of a number of genetic mutations underlying AI, the precise causal mechanisms have yet to be determined. Using a multi-disciplinary approach, we describe here a mis-sense mutation in the mouse Amelx gene resulting in a Y --> H substitution in the tri-tyrosyl domain of the enamel extracellular matrix protein amelogenin. The enamel in affected animals phenocopies human X-linked AI where similar mutations have been reported. Animals affected by the mutation have severe defects of enamel bio-mineralization associated with absence of full-length amelogenin protein in the developing enamel matrix, loss of ameloblast phenotype, increased ameloblast apoptosis and formation of multi-cellular masses. We present evidence to demonstrate that affected ameloblasts express but fail to secrete full-length amelogenin leading to engorgement of the endoplasmic reticulum/Golgi apparatus. Immunohistochemical analysis revealed accumulations of both amelogenin and ameloblastin in affected cells. Co-transfection of Ambn and mutant Amelx in a eukaryotic cell line also revealed intracellular abnormalities and increased cytotoxicity compared with cells singly transfected with wild-type Amelx, mutant Amelx or Ambn or co-transfected with both wild-type Amelx and Ambn. We hypothesize that intracellular protein-protein interactions mediated via the amelogenin tri-tyrosyl motif are a key mechanistic factor underpinning the molecular pathogenesis in this example of AI. This study therefore successfully links phenotype with underlying genetic lesion in a relevant murine model for human AI.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Mutação de Sentido Incorreto / Doenças Genéticas Ligadas ao Cromossomo X / Proteínas do Esmalte Dentário / Amelogenina / Amelogênese Imperfeita Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2010 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Mutação de Sentido Incorreto / Doenças Genéticas Ligadas ao Cromossomo X / Proteínas do Esmalte Dentário / Amelogenina / Amelogênese Imperfeita Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2010 Tipo de documento: Article