AMELX mutations and genotype-phenotype correlation in x-linked amelogenesis imperfecta
Yükleniyor...
Dosyalar
Tarih
2024
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
AMELX 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.
Açıklama
Anahtar Kelimeler
ER stress, Ameloblast, Amelogenin, Apoptosis, Biomineralization, Dental enamel, Iyonization, Protein secretion, Signal peptide, Unfolded protein response
Kaynak
International Journal of Molecular Sciences
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
25
Sayı
11
Künye
Wang, 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/ijms25116132
