Wang, Shih-KaiZhang, HongLin, Hua-ChiehWang, Yin-LinLin, Shu-ChunSeymen, FigenKoruyucu, MineSimmer, James P.Hu, Jan C.-C.2024-07-092024-07-092024Wang, S.-K., Zhang, H., Lin, H.-C., Wang, Y.-L., Lin, S.-C., Seymen, F., Koruyucu, M., Simmer, J. P., Hu, J. C.-C. (2024). AMELX mutations and genotype-phenotype correlation in x-linked amelogenesis imperfecta. International Journal of Molecular Sciences, 25(11). 10.3390/ijms251161321422-0067https://hdl.handle.net/20.500.12939/4735AMELX 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 AMELX 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 AMELX 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 AMELX-associated AI: While amorphic mutations, including large deletions and 5' truncations, of AMELX 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.eninfo:eu-repo/semantics/openAccessER stressAmeloblastAmelogeninApoptosisBiomineralizationDental enamelIyonizationProtein secretionSignal peptideUnfolded protein responseArticle25112-s2.0-85195834132Q1WOS:001246886100001Q1