PTH1R – Primary Failure of Tooth Eruption

Primary failure of tooth eruption (PFE) (MONDO:0007434) is a rare autosomal dominant non-syndromic disorder characterized by arrested eruption of posterior teeth leading to lateral open bite malocclusion. Heterozygous variants in PTH1R (HGNC:9608) disrupt parathyroid hormone/parathyroid hormone-related peptide receptor signaling in dental follicle and alveolar bone, preventing normal tooth emergence. Early molecular diagnosis is critical to avoid ineffective orthodontic and surgical interventions and to guide multidisciplinary management.

Familial, nonsyndromic PFE was first linked to heterozygous truncating PTH1R mutations in 15 affected individuals from four multiplex pedigrees (c.463G>T (p.Glu155Ter), c.543+1G>A, c.1050-3C>G) (PMID:19061984). Subsequent linkage and exome resequencing in two Japanese families (8 affected) identified missense variants (c.395C>G (p.Pro132Arg), c.1148G>A (p.Arg383Gln)) segregating with PFE (PMID:21404329). Large-scale screening of 70 index PFE cases uncovered 30 unique PTH1R variants (12 pathogenic truncating/splice, 18 missense) with high penetrance in posterior dentition (PMID:23771181). More recent cohorts (43 cases) confirmed novel intronic and exonic variants, improving diagnostic yield when patients are carefully phenotyped (PMID:39327493).

The PTH1R variant spectrum in PFE includes >40 unique alleles: nonsense and frameshift mutations leading to premature truncation, splice-site disruptions, and missense substitutions targeting conserved residues in transmembrane and intracellular domains. A recurrent truncating allele c.1093del (p.Val365fs) has been reported in multiple European families. Incomplete penetrance has been documented (e.g., mother carrying c.505T>A (p.Tyr169Ter) without clinical PFE) (PMID:30904994).

Functional assays in HEK293 and Xenopus oocytes demonstrate that PTH1R PFE-associated mutants exhibit reduced cell surface expression and severely impaired cAMP generation in response to PTH(1-34), consistent with haploinsufficiency (PMID:27898723; PMID:35720667). Rescue of cAMP signaling by inverse agonists in Jansen metaphyseal chondrodysplasia mouse models supports receptor LOF as the disease mechanism and underlines the specificity of PFE-associated alleles for tooth eruption pathways (PMID:31693237).

No conflicting data dispute the PTH1R–PFE association. Activating homozygous PTH1R mutations cause distinct skeletal syndromes (e.g., Blomstrand chondrodysplasia, Jansen metaphyseal chondrodysplasia), highlighting allele-specific phenotypic outcomes but not refuting haploinsufficiency as the driver of PFE.

Integration of genetic, segregation, and functional evidence establishes a definitive AD gene–disease relationship. PTH1R testing in patients with clinical PFE enables precise diagnosis, avoids unnecessary orthodontic interventions, and informs long-term multidisciplinary care.

Key Take-Home: Heterozygous loss-of-function PTH1R variants are a definitive cause of primary failure of tooth eruption; molecular testing should be integrated into early diagnostic workflows to guide targeted management.

References

• American Journal of Human Genetics • 2008 • PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption PMID:19061984
• Journal of Bone and Mineral Research • 2011 • Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese PMID:21404329
• Clinical Oral Investigations • 2014 • Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption PMID:23771181
• PLoS One • 2016 • PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling PMID:27898723
• European Archives of Paediatric Dentistry • 2019 • Primary failure of eruption of teeth in two siblings with a novel mutation in the PTH1R gene PMID:30904994
• European Journal of Human Genetics • 2024 • New Insight into the genotype-phenotype correlation of PTH1R variants and primary failure of tooth eruption on an Italian Cohort PMID:39327493

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