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 of insufficient quantity and/or altered quality, impacting structural content, surface integrity and coloration. Heterozygous mutations in result in hypoplastic AI without other...

Full description

Saved in:
Bibliographic Details
Published in:Biomedicines 2021-04, Vol.9 (5), p.456
Main Authors: Kim, Youn Jung, Lee, Yejin, Zhang, Hong, Wright, John Timothy, Simmer, James P, Hu, Jan C-C, Kim, Jung-Wook
Format: Article
Language:English
Subjects:
5' Untranslated Regions
Amelogenesis imperfecta
Amino acid sequence
Antibodies
Bioinformatics
Cloning
Coloration
Communication
Dental enamel
ENAM
Gene expression
Genes
Genomes
Genomics
hereditary enamel defects
intron retention
mRNA
Mutagenesis
Mutants
Mutation
Phenotypes
Protein expression
splicing donor site mutation
Translation
Translation initiation
whole exome sequencing
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Amelogenesis imperfecta (AI) is a collection of rare genetic conditions affecting tooth enamel. The affected enamel can be of insufficient quantity and/or altered quality, impacting structural content, surface integrity and coloration. Heterozygous mutations in result in hypoplastic AI without other syndromic phenotypes, with variable expressivity and reduced penetrance, unlike other AI-associated genes. In this study, we recruited a Caucasian family with hypoplastic AI. Mutational analysis (using whole exome sequencing) revealed a splicing donor site mutation (NM_031889.3: c. -61 + 1G > A). Mutational effects caused by this variant were investigated with a minigene splicing assay and in vitro expression analysis. The mutation resulted in a retention of intron 1 and exon 2 (a normally skipped exon), and this elongated 5' UTR sequence attenuated the translation from the mutant mRNA. Structure and translation predictions raised the possibility that the long complex structures-especially a hairpin structure located right before the translation initiation codon of the mutant mRNA-caused reduced protein expression. However, there could be additional contributing factors, including additional uORFs. For the first time, we determined that a mutation altered the 5' UTR, but maintained the normal coding amino acid sequence, causing hypoplastic AI.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines9050456