WDR72 – Amelogenesis Imperfecta

Amelogenesis imperfecta (AI) is a heterogeneous group of inherited enamel formation defects characterized by hypomaturation, hypomineralization, and discoloration of the tooth enamel. WDR72 (HGNC:26790), encoding WD repeat–containing protein 72, has been implicated in autosomal recessive AI, type IIA3 (MONDO:0019507), through multiple independent studies identifying biallelic loss‐of‐function variants. The enamel phenotype typically presents as structurally normal thickness with severe hypomineralization, orange‐brown staining, and rapid attrition, while extra‐dental features are generally absent or subtle.

Genetic Evidence: Autosomal recessive inheritance of AI due to WDR72 variants is supported by nine unrelated families with ten affected probands. Two siblings from a consanguineous Turkish pedigree were homozygous for a novel nonsense mutation c.997A>T (p.Lys333Ter) (PMID:23293580). Two independent families from Mexico and Turkey each harbored a homozygous dinucleotide deletion c.1467_1468delAT (p.Val491AspfsTer8), with perfect segregation in each kindred (PMID:20938048). Six additional families identified by exome sequencing carry biallelic WDR72 mutations, including stop‐gains, frameshifts, a 62‐kb genomic deletion, and a missense change, all co‐segregating with the AI phenotype (PMID:30779877). Total segregation evidence includes ten affected relatives across these cohorts.

Variant Spectrum: Pathogenic variants in WDR72 are predominantly loss‐of‐function: nonsense (e.g., p.Lys333Ter[PMID:23293580]; p.Trp126Ter[PMID:30779877]), frameshift (e.g., c.1467_1468delAT (p.Val491AspfsTer8)[PMID:20938048]), multi‐exonic deletions (g.35441_97578del[PMID:30779877]; large exon deletions[PMID:27259663]), and rare missense (p.Gly422Val[PMID:30779877]). No recurrent founder alleles have been established.

Functional Evidence: A novel homozygous nonsense variant p.Ser783Ter was associated with reduced mineral density and altered inter‐rod enamel structure by scanning electron microscopy and microradiography of deciduous teeth (PMID:21196691). Structural modeling and a Wdr72–/– mouse model demonstrated hypomineralized enamel, ameloblast morphological defects, and impaired amelogenin removal during maturation (PMID:25008349). A custom MLPA assay confirmed multi‐exonic WDR72 deletions, supporting loss‐of‐function as the disease mechanism (PMID:27259663). Subcellular localization studies revealed WDR72 recruitment to the Golgi via a C-terminal CAAX motif, with AI-associated C-terminal truncations abolishing Golgi targeting (PMID:35301423).

Mechanism & Clinical Integration: WDR72 appears to function in endocytic vesicle trafficking during the enamel maturation stage, facilitating amelogenin clearance. Loss‐of‐function mutations disrupt this process, resulting in hypomaturation and hypomineralization of enamel. The consistent autosomal recessive segregation and concordant in vivo and in vitro data establish a definitive gene‐disease relationship. Genetic testing for WDR72 should be incorporated into AI diagnostic panels to guide prognosis and management of affected individuals.

References

• Molecular syndromology • 2012 • A Novel Homozygous WDR72 Mutation in Two Siblings with Amelogenesis Imperfecta and Mild Short Stature. PMID:23293580
• Journal of Dental Research • 2010 • Novel WDR72 mutation and cytoplasmic localization. PMID:20938048
• Journal of Dental Research • 2019 • WDR72 Mutations Associated with Amelogenesis Imperfecta and Acidosis. PMID:30779877
• Cells, Tissues, Organs • 2011 • Hypomaturation amelogenesis imperfecta due to WDR72 mutations: a novel mutation and ultrastructural analyses of deciduous teeth. PMID:21196691
• Matrix Biology • 2014 • WDR72 models of structure and function: a stage-specific regulator of enamel mineralization. PMID:25008349
• Gene • 2016 • Identification of the first multi-exonic WDR72 deletion in isolated amelogenesis imperfecta, and generation of a WDR72-specific copy number screening tool. PMID:27259663
• Scientific Reports • 2022 • Identification of the C-terminal region in Amelogenesis Imperfecta causative protein WDR72 required for Golgi localization. PMID:35301423

Evidence Based Scoring (AI generated)