Alteration of Exon Definition Causes Amelogenesis Imperfecta

Author:

Kim Y.J.1,Kang J.2,Seymen F.3,Koruyucu M.3,Zhang H.4,Kasimoglu Y.3,Bayram M.5,Tuna-Ince E.B.3,Bayrak S.6,Tuloglu N.6,Hu J.C.-C.4,Simmer J.P.4,Kim J.-W.12ORCID

Affiliation:

1. Department of Molecular Genetics & Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea

2. Department of Pediatric Dentistry & Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea

3. Department of Pedodontics, Faculty of Dentistry, Istanbul University, Istanbul, Turkey

4. Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA

5. Department of Pedodontics, Faculty of Dentistry, Istanbul Medipol University, Istanbul, Turkey

6. Department of Pediatric Dentistry, Faculty of Dentistry, University of Eskisehir Osmangazi, Eskisehir, Turkey

Abstract

Amelogenesis imperfecta (AI) is a collection of genetic disorders affecting the quality and/or quantity of tooth enamel. More than 20 genes are, so far, known to be responsible for this condition. In this study, we recruited 3 Turkish families with hypomaturation AI. Whole-exome sequence analyses identified disease-causing mutations in each proband, and these mutations cosegregated with the AI phenotype in all recruited members of each family. The AI-causing mutations in family 1 were a novel AMELX mutation [NM_182680.1:c.143T>C, p.(Leu48Ser)] in the proband and a novel homozygous MMP20 mutation [NM_004771.3:c.616G>A, p.(Asp206Asn)] in the mother of the proband. Previously reported compound heterozygous MMP20 mutations [NM_004771.3:c.103A>C, p.(Arg35=) and c.389C>T, p.(Thr130Ile)] caused the AI in family 2 and family 3. Minigene splicing analyses revealed that the AMELX missense mutation increased exonic definition of exon 4 and the MMP20 synonymous mutation decreased exonic definition of exon 1. These mutations would trigger an alteration of exon usage during RNA splicing, causing the enamel malformations. These results broaden our understanding of molecular genetic pathology of tooth enamel formation.

Funder

national institute of dental and craniofacial research

national research foundation of korea

Publisher

SAGE Publications

Subject

General Dentistry

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