LRP6 – Tooth Agenesis

The low-density lipoprotein receptor–related protein 6 (LRP6) is a transmembrane Wnt co-receptor essential for canonical Wnt/β-catenin signaling in tooth development. Heterozygous loss-of-function and missense variants in LRP6 have been implicated in autosomal dominant tooth agenesis (oligodontia), a severe form of congenital absence of permanent teeth.

Multiple independent cohorts have identified rare LRP6 variants in patients with nonsyndromic and familial tooth agenesis. Five probands with frameshift and splice-site mutations were reported in a targeted resequencing study of tooth agenesis (67 cases) (PMID:26963285). Four unrelated oligodontia probands carried truncating and missense LRP6 variants detected by exome sequencing (20 cases) (PMID:26387593). An additional four heterozygous LRP6 mutations were found in 77 oligodontia patients (PMID:33164649). Furthermore, 21 familial tooth agenesis cases harbored 15 distinct LRP6 loss-of-function alleles (PMID:34834569).

All reported LRP6 variants segregate with an autosomal dominant tooth agenesis phenotype. Multigenerational segregation was documented in at least four families (PMID:26963285; PMID:26387593), and one missense change arose de novo.

Functional assays consistently demonstrate that LRP6 pathogenic alleles impair Wnt/β-catenin signaling. TOP-/FOP-flash reporter studies of patient-derived missense and truncating variants showed markedly reduced pathway activation (PMID:26387593; PMID:33164649). Structural modeling predicts destabilization of LRP6 propeller domains, and murine in situ hybridization confirms dynamic Lrp6 expression in dental epithelium and mesenchyme during tooth morphogenesis.

The mechanism of pathogenicity is consistent with haploinsufficiency: truncating variants reduce cell-surface LRP6 levels and compromise Wnt co-receptor function, leading to failure of tooth bud development.

No studies have disputed the association of LRP6 with tooth agenesis, and alternative gene etiologies have been excluded in most reported families.

Collectively, the genetic spectrum, segregation data, and concordant functional evidence support a Strong clinical validity classification for LRP6 in autosomal dominant tooth agenesis. Key take-home: inclusion of LRP6 in diagnostic gene panels enhances detection of oligodontia-causing variants and informs precision dental management.

References

• Genetics in medicine • 2016 • Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. PMID:26963285
• American journal of human genetics • 2015 • Loss-of-Function Mutations in the WNT Co-receptor LRP6 Cause Autosomal-Dominant Oligodontia. PMID:26387593
• Journal of dental research • 2021 • Lrp6 Dynamic Expression in Tooth Development and Mutations in Oligodontia. PMID:33164649
• Journal of personalized medicine • 2021 • Synergistic Mutations of LRP6 and WNT10A in Familial Tooth Agenesis. PMID:34834569

Evidence Based Scoring (AI generated)