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Human Molecular Genetics Advance Access originally published online on January 13, 2005
Human Molecular Genetics 2005 14(5):575-583; doi:10.1093/hmg/ddi054
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Human Molecular Genetics, Vol. 14, No. 5 © Oxford University Press 2005; all rights reserved

Enamelin (Enam) is essential for amelogenesis: ENU-induced mouse mutants as models for different clinical subtypes of human amelogenesis imperfecta (AI)

Hiroshi Masuya1, Kunihiko Shimizu2, Hideki Sezutsu3,4, Yoshiyuki Sakuraba3, Junko Nagano1, Aya Shimizu1, Naomi Fujimoto3, Akiko Kawai1, Ikuo Miura1, Hideki Kaneda1, Kimio Kobayashi1, Junko Ishijima1, Takahide Maeda2, Yoichi Gondo3, Tetsuo Noda1, Shigeharu Wakana1 and Toshihiko Shiroishi1,*

1Mouse Functional Genomics Research Group, RIKEN GSC, 3-1-1 Kouyadai, Tsukuba, Ibaraki 305-0074, Japan, 2Department of Pediatric Dentistry, Nihon University School of Dentistry at Matsudo, Japan, 3Population and Quantitative Genomics Team, RIKEN GSC, Japan and 4Insect Gene Engineering Laboratory, Insect Biotechnology and Sericology Department, Institute of Insect and Animal Sciences, National Institute of Agrobiological Sciences, Japan

* To whom correspondence should be addressed. Tel: +81 298369017; Fax: +81 298363616; Email: tshirois{at}lab.nig.ac.jp

Received November 11, 2004; Revised December 22, 2004; Accepted January 4, 2005

Amelogenesis imperfecta (AI) is a group of commonly inherited defects of dental enamel formation, which exhibits marked genetic and clinical heterogeneity. The genetic basis of this heterogeneity is still poorly understood. Enamelin, the affected gene product in one form of AI (AIH2), is an extracellular matrix protein that is one of the components of enamel. We isolated three ENU-induced dominant mouse mutations, M100395, M100514 and M100521, which caused AI-like phenotypes in the incisors and molars of the affected individuals. Linkage analyses mapped each of the three mutations to a region of chromosome 5 that contained the genes encoding enamelin (Enam) and ameloblastin (Ambn). Sequence analysis revealed that each mutation was a single-base substitution in Enam. M100395 (EnamRgsc395) and M100514 (EnamRgsc514) were putative missense mutations that caused S to I and E to G substitutions at positions 55 and 57 of the translated protein, respectively. EnamRgsc395 and EnamRgsc514 heterozygotes showed severe breakage of the enamel surface, a phenotype that resembled local hypoplastic AI. The M100521 mutation (EnamRgsc521) was a T to A substitution at the splicing donor site in intron 4. This mutation resulted in a frameshift that gave rise to a premature stop codon. The transcript of the EnamRgsc521 mutant allele was degraded, indicating that EnamRgsc521 is a loss-of-function mutation. EnamRgsc521 heterozygotes showed a hypomaturation-type AI phenotype in the incisors, possibly due to haploinsufficiency of Enam. EnamRgsc521 homozygotes showed complete loss of enamel on the incisors and the molars. Thus, we report here that the Enam gene is essential for amelogenesis, and that mice with different point mutations at Enam may provide good animal models to study the different clinical subtypes of AI.


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