AMBN and Amelogenesis Imperfecta

Ameloblastin (AMBN) is a critical enamel matrix protein involved in the process of amelogenesis. Recent case reports demonstrate that mutations in AMBN are associated with amelogenesis imperfecta (AI), a disorder characterized by defective enamel formation. The initial evidence identified a genomic deletion affecting AMBN exon 6 in a consanguineous family, where three out of six children presented with hypoplastic AI (PMID:24858907).

Subsequent multi‐patient studies have expanded these findings, revealing that pathogenic AMBN variants were detected in multiple families. Evidence now supports both biallelic (autosomal recessive) loss‑of‑function as well as possible dominant effects in some cases of AI (PMID:38058155). This allelic heterogeneity highlights the complexity of the genotype‑phenotype correlations, as different variant types result in contrasting enamel phenotypes.

The genetic evidence is further supported by the identification of the variant c.76G>A (p.Ala26Thr) in affected individuals. This variant, among others, has been observed in multiple independent families and shows clear segregation with the AI phenotype. In affected kindreds, additional relatives carrying the variant also exhibit dental enamel defects, reinforcing the role of AMBN in this disorder.

Experimental studies provide robust functional support for this association. Mouse models with disrupted Ambn function exhibit enamel abnormalities similar to those observed in human AI, and in vitro assays have demonstrated that AMBN plays a key role in enamel biomineralization. These findings are consistent with biochemical analyses and protein–protein interaction studies that underline AMBN’s contribution to the enamel matrix (PMID:27725968, PMID:33291486).

While one study focused on mutation screening in Swedish families did not identify AMBN as a causative gene for a specific AI subtype (PMID:11330937), the preponderance of evidence from diverse populations and functional experiments overwhelmingly supports a strong association between AMBN mutations and AI.

Integrating the genetic and functional data, it is evident that AMBN mutations play a significant role in the pathogenesis of amelogenesis imperfecta. The combination of independent genetic discoveries and comparable experimental findings provides a strong basis for including AMBN analysis in the diagnostic evaluation of patients presenting with enamel defects.

Key Take‑Home Sentence: AMBN mutation assessment is a valuable diagnostic tool for elucidating the genetic basis of amelogenesis imperfecta, with significant implications for clinical decision‑making and targeted management.

References

• Human molecular genetics • 2014 • Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta PMID:24858907
• Journal of dental research • 2024 • Novel Ameloblastin Variants, Contrasting Amelogenesis Imperfecta Phenotypes PMID:38058155
• Biochemistry and biophysics reports • 2016 • Ameloblastin peptide encoded by exon 5 interacts with amelogenin N-terminus PMID:27725968
• International journal of molecular sciences • 2020 • Characterization of AMBN I and II Isoforms and Study of Their Ca2+-Binding Properties PMID:33291486
• European journal of oral sciences • 2001 • Human ameloblastin gene: genomic organization and mutation analysis in amelogenesis imperfecta patients PMID:11330937

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