AMELX Mutations and Genotype–Phenotype Correlation in X-Linked Amelogenesis Imperfecta
Journal
International journal of molecular sciences
Journal Volume
25
Journal Issue
11
Start Page
Article number 6132
ISSN
1422-0067
Date Issued
2024-06-01
Author(s)
Zhang, Hong
Lin, Hua-Chieh
Lin, Shu-Chun
Seymen, Figen
Koruyucu, Mine
Simmer, James P
Hu, Jan C-C
Abstract
mutations cause X-linked amelogenesis imperfecta (AI), known as AI types IE, IIB, and IIC in Witkop's classification, characterized by hypoplastic (reduced thickness) and/or hypomaturation (reduced hardness) enamel defects. In this study, we conducted whole exome analyses to unravel the disease-causing mutations for six AI families. Splicing assays, immunoblotting, and quantitative RT-PCR were conducted to investigate the molecular and cellular effects of the mutations. Four pathogenic variants (NM_182680.1:c.2T>C; c.29T>C; c.77del; c.145-1G>A) and a whole gene deletion (NG_012494.2:g.307534_403773del) were identified. The affected individuals exhibited enamel malformations, ranging from thin, poorly mineralized enamel with a "snow-capped" appearance to severe hypoplastic defects with minimal enamel. The c.145-1G>A mutation caused a -1 frameshift (NP_001133.1:p.Val35Cysfs*5). Overexpression of c.2T>C and c.29T>C demonstrated that mutant amelogenin proteins failed to be secreted, causing elevated endoplasmic reticulum stress and potential cell apoptosis. This study reveals a genotype-phenotype relationship for -associated AI: While amorphic mutations, including large deletions and 5' truncations, of cause hypoplastic-hypomaturation enamel with snow-capped teeth (AI types IIB and IIC) due to a complete loss of gene function, neomorphic variants, including signal peptide defects and 3' truncations, lead to severe hypoplastic/aplastic enamel (AI type IE) probably caused by "toxic" cellular effects of the mutant proteins.
Subjects
ER stress
ameloblast
amelogenin
apoptosis
biomineralization
dental enamel
lyonization
protein secretion
signal peptide
unfolded protein response
Type
journal article