Translational Attenuation by an Intron Retention in the 5′ UTR of ENAM Causes Amelogenesis Imperfecta

Amelogenesis imperfecta (AI) is a collection of rare genetic conditions affecting tooth enamel. The affected enamel can be insufficient quantity and/or altered quality, impacting structural content, surface integrity and coloration. Heterozygous mutations in ENAM result hypoplastic AI without other syndromic phenotypes, with variable expressivity reduced penetrance, unlike AI-associated genes. In this study, we recruited Caucasian family AI. Mutational analysis (using whole exome sequencing) revealed splicing donor site mutation (NM_031889.3: c. −61 + 1G > A). effects caused by variant were investigated minigene assay vitro expression analysis. resulted retention intron 1 exon 2 (a normally skipped exon), elongated 5′ UTR sequence attenuated the translation from mutant mRNA. Structure predictions raised possibility that long complex structures—especially hairpin structure located right before initiation codon mRNA—caused protein expression. However, there could additional contributing factors, including uORFs. For first time, determined UTR, but maintained normal coding amino acid sequence, causing