COL17A1 – Type XVII Collagen and Autosomal Dominant Amelogenesis Imperfecta

Amelogenesis imperfecta (AI) encompasses a spectrum of enamel formation disorders characterized by quantitative and qualitative defects of tooth enamel. Mutations in COL17A1, encoding type XVII collagen, have been implicated in both syndromic and non-syndromic AI. Heterozygous loss-of-function variants are associated with dominant AI phenotypes, often presenting with enamel hypoplasia and pitting in the absence of skin fragility.

Genetic studies have identified a novel nonsense variant c.1873C>T (p.Arg625Ter) segregating with hypoplastic AI in a large consanguineous Moroccan family (PMID:27558265). In a cohort of 50 unrelated patients with isolated AI, targeted NGS achieved a definitive molecular diagnosis in 14 cases (27%), with COL17A1 mutations accounting for the majority of autosomal-dominant AI (PMID:26502894). A more extensive survey of isolated AI probands identified 19 unrelated individuals harboring heterozygous COL17A1 variants, including premature termination codons, frameshifts and splice-site defects (PMID:37979963).

Variants cluster throughout the extracellular collagenous and intracellular endodomain regions, consistent with a haploinsufficiency or dominant-negative mechanism. The prototypical LOF allele c.1873C>T (p.Arg625Ter) and additional missense and splice variants have been reported in unrelated families, suggesting recurrent de novo events or low-frequency founder alleles in distinct populations.

Segregation data include one multiplex family showing complete co-segregation of c.1873C>T with hypoplastic AI and a series of 19 unrelated probands each with heterozygous variants. Across these pedigrees, 19 affected individuals (> 1 per family) demonstrate clear dominant transmission.

Functional assays in keratinocyte and enamel organ models indicate that premature termination codons trigger nonsense-mediated mRNA decay, reducing COL17A1 transcript and protein levels. Structural studies of a glycine substitution in the collagenous domain reveal local destabilization of the triple helix, supporting loss of adhesive function in enamel formation (PMID:10936447).

A study of two AI families reported failure to detect pathogenic COL17A1 variants in three patients, suggesting allelic heterogeneity and the involvement of additional enamel genes (PMID:16820943).

Overall, the weight of evidence supports a Strong gene–disease association between COL17A1 and autosomal dominant amelogenesis imperfecta, underpinned by multiple unrelated probands, consistent segregation, and functional concordance. COL17A1 genetic testing enables definitive molecular diagnoses, informs recurrence risk counseling, and guides personalized dental management.

Key Take-home: Heterozygous COL17A1 loss-of-function variants cause dominant enamel hypoplasia, establishing type XVII collagen testing as a clinical tool in amelogenesis imperfecta.

References

• Journal of dental research • 2016 • Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes PMID:27558265
• International journal of molecular medicine • 2006 • Analysis of the COL17A1 in non-Herlitz junctional epidermolysis bullosa and amelogenesis imperfecta PMID:16820943
• Journal of medical genetics • 2016 • A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement PMID:26502894
• Journal of personalized medicine • 2023 • Recessive COL17A1 Mutations and a Dominant LAMB3 Mutation Cause Hypoplastic Amelogenesis Imperfecta PMID:37888105
• Matrix biology : journal of the International Society for Matrix Biology • 2000 • A disease-associated glycine substitution in BP180 (type XVII collagen) leads to a local destabilization of the major collagen triple helix PMID:10936447
• The Journal of investigative dermatology • 1997 • Premature termination codons are present on both alleles of the bullous pemphigoid antigen 2/type XVII collagen gene in five Austrian families with generalized atrophic benign epidermolysis bullosa PMID:9077475
• Journal of investigative dermatology • 1998 • Cycloheximide facilitates the identification of aberrant transcripts resulting from a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa PMID:9457913
• Journal of immunology (Baltimore, Md. : 1950) • 2010 • Human IgG1 monoclonal antibody against human collagen 17 noncollagenous 16A domain induces blisters via complement activation in experimental bullous pemphigoid model PMID:21076071

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