VPS4B – Dentin Dysplasia Type I

Dentin dysplasia type I (DD-I) is an autosomal dominant disorder characterized by rootless teeth (HP:0011072) and normal enamel formation. Affected individuals present with shortened or absent roots, often leading to premature tooth loss and associated morbidity. The genetic etiology is heterogeneous, and recent studies have implicated VPS4B as a candidate gene in DD-I pathogenesis.

Genetic evidence for VPS4B in DD-I is currently limited. A single autosomal dominant proband was reported to harbor a splice-site mutation in VPS4B (IVS7+>G) associated with rootless teeth and impaired dental follicle cell (DFC) function (PMID:32737282). No additional unrelated families or segregation data have been described to date.

Variant spectrum in DD-I remains narrow. To date, only a single splicing alteration in VPS4B has been linked to the human phenotype. Broader mutational screening has not yet identified recurrent or founder alleles in diverse populations.

Functional assessment of patient-derived DFCs demonstrated that the VPS4B splice mutation led to increased proliferation rates and markedly reduced osteogenic differentiation, as evidenced by diminished alizarin red and alkaline phosphatase staining and downregulation of ALP, BSP, OCN, and RUNX2 at RNA and protein levels (PMID:32737282). These findings support a loss-of-function mechanism impairing root formation and bone remodeling.

Conflicting evidence arises from a Vps4b heterozygous mouse model in which adult mice did not exhibit dental or bone abnormalities akin to human DD-I, suggesting species-specific differences in tooth development and questioning haploinsufficiency as the sole pathogenic mechanism (PMID:30634912).

Integration of genetic and functional data indicates that VPS4B splice mutations can disrupt osteogenic differentiation in human DFCs, consistent with DD-I phenotypes. However, the limited number of cases and lack of segregation or recurrence prevent a definitive classification. Additional familial studies and variant screening are needed to confirm VPS4B’s role in root development.

Key Take-home: VPS4B splice variants are candidate causes of autosomal dominant dentin dysplasia type I, with patient-derived cell assays demonstrating impaired osteogenesis, but further genetic validation is required for clinical implementation.

References

• International journal of oral science • 2020 • VPS4B mutation impairs the osteogenic differentiation of dental follicle cells derived from a patient with dentin dysplasia type I. PMID:32737282
• BMC genetics • 2019 • Vps4b heterozygous mice do not develop tooth defects that replicate human dentin dysplasia I. PMID:30634912

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