A novel brachydactyly type E syndrome caused by variants in helix 8 of the PTH1R

Simple item page
dc.catalogadorgrr
dc.contributor.author Monahan, Gavin
dc.contributor.authorHöppner, Jakob
dc.contributor.author Jüppner, Harald
dc.contributor.author Rick, Audrey
dc.contributor.authorMcNamara, Elyshia
dc.contributor.authorTee, William
dc.contributor.author Lay-Son, Guillermo
dc.contributor.author Contreras, Andy
dc.contributor.author Martínez, Alejandro
dc.contributor.author García, Cristián
dc.contributor.authorVildoso, Javiera
dc.contributor.authorGardella, Thomas J
dc.contributor.authorKamien, Benjamin
dc.contributor.authorGianina, Ravenscroft
dc.date.accessioned2025-10-09T18:49:41Z
dc.date.available2025-10-09T18:49:41Z
dc.date.issued2025
dc.description.abstractThe parathyroid hormone receptor 1 (PTH1R) transmits stimuli provided by parathyroid hormone (PTH) and PTH-related protein (PTHrP) and thus plays key roles in calcium and phosphate homeostasis as well as skeletal development. Variants in PTH1R have been linked to several conditions including Jansen's metaphyseal chondrodysplasia, Blomstrand chondrodysplasia, Primary Failure of Tooth Eruption and Eiken syndrome. Here, we report a novel skeletal phenotype identified in two unrelated families associated with PTH1R variants. The clinical features include brachydactyly type E (BDE), mild short stature, and dental anomalies. A novel heterozygous PTH1R substitution (p.E469K) was identified in affected members of Family 1, while the affected individual from Family 2 had a previously described heterozygous de novo substitution (p.E465K); these two mutated sites lie within helix 8 of the PTH1R. Cell-based assays revealed reduced cell surface expression, as well as impaired basal and PTH- or PTHrP-induced cAMP signaling responses for both mutants, as compared to WT-PTH1R. Introduction of the p.E469K substitution into humanized PTH1R mice resulted in mildly increased mineralization of bones in the paws as well as shortening of long bones. Our findings demonstrate a new skeletal phenotype associated with PTH1R variants and suggest that helix 8 of the receptor contributes to PTH1R expression and/or signaling during bone development.
dc.fechaingreso.objetodigital2025-10-09
dc.format.extent43 páginas
dc.fuente.origenORCID
dc.identifier.doi10.1093/jbmr/zjaf134
dc.identifier.eissn1523-4681
dc.identifier.issn0884-0431
dc.identifier.pubmedid41031626
dc.identifier.uri https://doi.org/10.1093/jbmr/zjaf134
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/106004
dc.language.isoen
dc.nota.accesocontenido completo
dc.revistaJournal of Bone and Mineral Research
dc.rightsacceso abierto
dc.rights.licenseCC BY-NC-ND 4.0 Attribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectPTH1R
dc.subjectGPCR
dc.subjectHelix 8
dc.subjectBrachydactyly
dc.subjectShort stature
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleA novel brachydactyly type E syndrome caused by variants in helix 8 of the PTH1R
dc.typepreprint
sipa.indexPubmed
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
zjaf134.pdf
Size:
1.65 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
1.98 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Artículos de revistas