Gavin Monahan, Jakob Höppner, Harald Jüppner, Audrey Rick, Elyshia McNamara, William Tee, Guillermo Lay-Son, Andy Contreras, Alejandro Martínez, Cristián García, Javiera Vildoso, Thomas J Gardella, Benjamin Kamien, Gianina Ravenscroft
{"title":"一种由PTH1R螺旋8变异引起的新型短指E型综合征。","authors":"Gavin Monahan, Jakob Höppner, Harald Jüppner, Audrey Rick, Elyshia McNamara, William Tee, Guillermo Lay-Son, Andy Contreras, Alejandro Martínez, Cristián García, Javiera Vildoso, Thomas J Gardella, Benjamin Kamien, Gianina Ravenscroft","doi":"10.1093/jbmr/zjaf134","DOIUrl":null,"url":null,"abstract":"<p><p>The 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.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A novel brachydactyly type E syndrome caused by variants in helix 8 of the PTH1R.\",\"authors\":\"Gavin Monahan, Jakob Höppner, Harald Jüppner, Audrey Rick, Elyshia McNamara, William Tee, Guillermo Lay-Son, Andy Contreras, Alejandro Martínez, Cristián García, Javiera Vildoso, Thomas J Gardella, Benjamin Kamien, Gianina Ravenscroft\",\"doi\":\"10.1093/jbmr/zjaf134\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The 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.</p>\",\"PeriodicalId\":185,\"journal\":{\"name\":\"Journal of Bone and Mineral Research\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Bone and Mineral Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/jbmr/zjaf134\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Bone and Mineral Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/jbmr/zjaf134","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
A novel brachydactyly type E syndrome caused by variants in helix 8 of the PTH1R.
The 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.
期刊介绍:
The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.