PTH1R – Blomstrand Chondrodysplasia

PTH1R encodes the parathyroid hormone receptor type 1, a class B G protein–coupled receptor essential for PTH/PTHrP signaling in chondrocytes and endochondral ossification. Autosomal recessive loss-of-function variants in PTH1R cause chondrodysplasia Blomstrand type, a neonatal lethal skeletal dysplasia characterized by extreme short-limb dwarfism and accelerated bone maturation. Genetic testing of PTH1R is critical for early diagnosis and family counseling in at-risk consanguineous pedigrees.

Clinical genetic evidence includes five unrelated probands from four families with homozygous inactivating PTH1R variants segregating with Blomstrand chondrodysplasia. A homozygous c.395C>T (p.Pro132Leu) variant was identified in a consanguineous family, abolishing ligand binding and downstream cAMP signaling (PMID:9832466). Multi-family studies revealed a homozygous nonsense variant c.310C>T (p.Arg104Ter), a frameshift c.996dup (p.Ala333fs), and a deep-intronic splice variant c.1049+29C>T in additional affected infants (PMID:17164305).

The variant spectrum includes missense (p.Pro132Leu), nonsense (p.Arg104Ter), frameshift (p.Ala333fs), and splice-creating intronic changes (c.1049+29C>T), all predicted to abolish receptor function. These variants are absent or extremely rare in population databases, consistent with a fully penetrant autosomal recessive mechanism.

Functional assays in COS-1 cells and patient-derived fibroblasts demonstrate that p.Pro132Leu and p.Arg104Ter mutants fail to bind PTH or PTHrP ligands, do not accumulate intracellular cAMP, and show normal cell-surface expression but complete loss of signaling capacity (PMID:9832466, PMID:17164305). These data establish haploinsufficiency is not tolerated and that complete receptor inactivation underlies disease pathogenesis.

No conflicting evidence for PTH1R involvement in Blomstrand chondrodysplasia has been reported. The concordance of genotype–phenotype segregation and robust functional validation meets ClinGen criteria for a strong gene–disease association.

Integration of genetic and experimental data confirms that autosomal recessive PTH1R loss-of-function variants cause chondrodysplasia Blomstrand type. Comprehensive PTH1R sequencing should be offered in neonates with extreme short-limb chondrodysplasia. Accurate molecular diagnosis enables reproductive counseling and may inform future therapeutic development targeting PTHR1 signaling.

References

• Endocrinology • 1998 • Inactivating mutation in the human parathyroid hormone receptor type 1 gene in Blomstrand chondrodysplasia PMID:9832466
• The Journal of clinical endocrinology and metabolism • 2007 • Novel mutations in the parathyroid hormone (PTH)/PTH-related peptide receptor type 1 causing Blomstrand osteochondrodysplasia types I and II PMID:17164305

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