PTH1R – Eiken syndrome

PTH1R encodes the parathyroid hormone receptor type 1, a G protein–coupled receptor that mediates parathyroid hormone (PTH) and PTH-related peptide (PTHrP) signaling essential for endochondral ossification and calcium homeostasis. Eiken syndrome (MONDO:0010803) is a rare autosomal recessive skeletal dysplasia characterized by delayed ossification of epiphyses, ischiopubic hypoplasia, supernumerary epiphyses, modeling abnormalities, and primary failure of tooth eruption.

1 Clinical Validity

Based on identification of bi-allelic missense variants in 3 unrelated probands across 2 families (one with c.103G>A (p.Glu35Lys) ([PMID:29987841]) and one with c.710T>A (p.Ile237Asn) in two patients ([PMID:39276366])), alongside concordant functional studies, the PTH1R–Eiken syndrome association is classified as Strong.

2 Genetic Evidence

Inheritance is autosomal recessive. Three probands from two unrelated families harbored homozygous PTH1R missense variants: c.103G>A (p.Glu35Lys) ([PMID:29987841]) and c.710T>A (p.Ile237Asn) ([PMID:39276366]). No additional segregating relatives were reported. All reported pathogenic alleles are missense changes affecting the extracellular or transmembrane domains and are rare in population databases.

3 Functional Evidence

In vitro assays in HEK293 reporter cells showed that Eiken-associated PTH1R variants (including p.Ile237Asn and previously reported p.Glu35Lys, p.Tyr134Ser) exhibit increased basal cAMP signaling with blunted responses to both PTH and PTHrP, and impaired β-arrestin2 recruitment, consistent with a receptor signaling defect underlying the skeletal and biochemical phenotype ([PMID:39276366]; [PMID:37268817]).

4 Integration & Conclusion

Collectively, genetic and experimental data support a mechanism in which hypomorphic homozygous PTH1R variants impair canonical PTH/PTHrP signaling, leading to delayed bone mineralization and PTH resistance in Eiken syndrome. Further case accumulation could solidify penetrance and variant spectrum.

Key Take-home: Biallelic PTH1R missense variants cause autosomal recessive Eiken syndrome by altering receptor signaling, informing molecular diagnosis and potential targeted therapies.

References

• Clinical genetics • 2018 • Report of second case and clinical and molecular characterization of Eiken syndrome. PMID:29987841
• Journal of bone and mineral research • 2024 • Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis. PMID:39276366

Evidence Based Scoring (AI generated)