International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

THURSDAY OCTOBER 21

3.00pm – 3.15pm

ENU-INDUCED MOUSE ENAMELIN (ENAM) MUTANTS AS MODELS FOR DIFFERENT CLINICAL SUBTYPES OF HUMAN AMELOGENESIS IMPERFECTA (AI).

Masuya H1, Shimizu K2, Sezutsu H1, Sakuraba Y1, Nagano J1, Shimizu A1, Fijimoto N1, Ishijima J1, Kaneda H1, Kobayashi K1, Maeda T2, Gondo Y1, Noda T1, Wakana S1, Shiroishi T1

1 RIKEN GSC, Tsukuba, Japan, 2 Nihon Univ, Matsudo, Japan

Amelogenesis imperfecta (AI) is a common group of inherited defects of dental enamel formation, which exhibit marked genetic and clinical heterogeneity. The genetic basis of this heterogeneity is still poorly understood. Enamelin is a extracellular matrix molecule that is one of components of enamel, and is affected in human AI (AIH2). We isolated three ENU-induced dominant mouse mutations, M100395, M100514 and M100521, which showed AI-like phenotypes in their incisors and molars. They were mapped closely to the genes encoding enamelin (Enam) and ameloblastin (Ambn) on chromosome 5. Sequence analyses revealed that all three mutations have base substitutions in the Enam. M100395 and M100514 have S to I and E to G (putative) missense mutations located near the N-terminal of enamelin protein. M100521 has a mutation at splicing donor site of intoron 4, which results in a flame shift and gives rise to the stop codon. We demonstrated that degradation of transcript of the mutant allele occurred in M100521. Thus, it appeared that M100521 is a loss-of-function type mutation of the Enam. Heterozygotes of M100521 showed hypomaturation-type AI-like phenotype in the incisors. It must be occurred by the haploinsufficiency of Enam. Homozygotes of M100521 showed complete loss of enamel in the incisor and the molar. By contrast, heterozygotes of M100395 and M100514 showed severe braking of the enamel surface, which is similar to local hypoplastic AI. Thus, we report here that the Enam gene is essential for amelogenesis, and that the mice with different point mutations at Enam represent different clinical subtypes of AI. These mouse mutants provide good animal models for study of variation of human AI.

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