ENAM – Hypoplastic Amelogenesis Imperfecta Type 1

Amelogenesis imperfecta type 1 (hypoplastic AI) is characterized by deficient enamel thickness and hardness. ENAM (HGNC:3344) variants have been reported in both autosomal recessive and dominant forms, with homozygous nonsense and heterozygous splicing mutations leading to variable penetrance (PMID:33864320; PMID:33922212). Across six families, eight affected individuals segregate ENAM alleles including nonsense, splice‐site, intronic retention, and frameshift indels, with cosegregation in parents and siblings (PMID:33864320; PMID:22414746; PMID:37985977; PMID:38716742).

Case reports identify a novel homozygous nonsense variant c.2078C>G (p.Ser693Ter) in exon 14, causing severely truncated enamelin in a proband whose heterozygous parents display mild to absent enamel defects (PMID:33864320). A canonical splice‐donor mutation c.534+1G>A and an intronic splice‐donor c.-61+1G>A lead to exon skipping or intron retention with translational attenuation in heterozygotes presenting hypoplastic AI (PMID:22414746; PMID:33922212). A second intronic splice‐site mutation c.123+1G>A was confirmed in a family with father–daughter transmission of hypoplastic‐hypomature AI (PMID:37985977).

Functional studies demonstrate that these ENAM mutations disrupt protein secretion, alter 3D structure, and impair enamel matrix formation. Minigene splicing assays confirm aberrant transcript products, structural modeling predicts loss of GT‐A–like domains, and overexpression of mutant ENAM in vitro causes endoplasmic reticulum stress and ameloblast apoptosis (PMID:33922212; PMID:38716742). In situ hybridization of mouse Enam and CRISPR/Cas9 knockout models corroborate secretory‐stage ameloblast expression and downregulation of enamel mineralization genes upon Enam loss (PMID:25815730).

Mechanistically, ENAM haploinsufficiency and proteinopathy underlie both hypoplastic and hypomaturation phenotypes, with truncated proteins forming aggregates that impede wild-type secretion. The concordance of genetic segregation and functional assays across multiple variant classes supports a moderate to strong gene–disease relationship.

Key Take-home: ENAM variants spanning nonsense, splicing, and frameshift mutations reliably cause hypoplastic AI via disrupted enamelin secretion and ameloblast pathology, informing molecular diagnosis and genetic counseling.

References

• Oral diseases • 2022 • A novel ENAM mutation causes hypoplastic amelogenesis imperfecta. PMID:33864320
• Cells, tissues, organs • 2012 • Molecular characterization of amelogenesis imperfecta in Chinese patients. PMID:22414746
• Biomedicines • 2021 • Translational Attenuation by an Intron Retention in the 5' UTR of ENAM Causes Amelogenesis Imperfecta. PMID:33922212
• BMC oral health • 2023 • Splicing mutations in AMELX and ENAM cause amelogenesis imperfecta. PMID:37985977
• Journal of dental research • 2024 • ENAM Mutations Can Cause Hypomaturation Amelogenesis Imperfecta. PMID:38716742
• PloS one • 2015 • Transcriptional factor DLX3 promotes the gene expression of enamel matrix proteins during amelogenesis. PMID:25815730

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