Brygida Bisikirska, Rossella Labella, Alvaro Cuesta-Dominguez, Na Luo, Jessica De Angelis, Ioanna Mosialou, Chyuan-Sheng Lin, David Beck, Sneh Lata, Peter Timothy Shyu, Donald J. McMahon, Edward Guo, Jacob Hagen, Wendy K. Chung, Elizabeth Shane, Adi Cohen, Stavroula Kousteni
{"title":"褪黑激素受体 1A 变异是特发性骨质疏松症的遗传原因","authors":"Brygida Bisikirska, Rossella Labella, Alvaro Cuesta-Dominguez, Na Luo, Jessica De Angelis, Ioanna Mosialou, Chyuan-Sheng Lin, David Beck, Sneh Lata, Peter Timothy Shyu, Donald J. McMahon, Edward Guo, Jacob Hagen, Wendy K. Chung, Elizabeth Shane, Adi Cohen, Stavroula Kousteni","doi":"10.1126/scitranslmed.adj0085","DOIUrl":null,"url":null,"abstract":"<div >Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A (<i>MTNR1A</i>) with a potential pathogenic outcome. A rare <i>MTNR1A</i> variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an <i>MTNR1A</i> variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [<i>MTNR1A</i>c.184+1G>T (<i>MTNR1A</i><sup><i>c.</i>184+1G>T</sup>)] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that <i>MTNR1A</i> mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the <i>MTNR1A</i> variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 769","pages":""},"PeriodicalIF":15.8000,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis\",\"authors\":\"Brygida Bisikirska, Rossella Labella, Alvaro Cuesta-Dominguez, Na Luo, Jessica De Angelis, Ioanna Mosialou, Chyuan-Sheng Lin, David Beck, Sneh Lata, Peter Timothy Shyu, Donald J. McMahon, Edward Guo, Jacob Hagen, Wendy K. Chung, Elizabeth Shane, Adi Cohen, Stavroula Kousteni\",\"doi\":\"10.1126/scitranslmed.adj0085\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A (<i>MTNR1A</i>) with a potential pathogenic outcome. A rare <i>MTNR1A</i> variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an <i>MTNR1A</i> variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [<i>MTNR1A</i>c.184+1G>T (<i>MTNR1A</i><sup><i>c.</i>184+1G>T</sup>)] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that <i>MTNR1A</i> mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the <i>MTNR1A</i> variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":\"16 769\",\"pages\":\"\"},\"PeriodicalIF\":15.8000,\"publicationDate\":\"2024-10-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.adj0085\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adj0085","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis
Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A (MTNR1A) with a potential pathogenic outcome. A rare MTNR1A variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an MTNR1A variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [MTNR1Ac.184+1G>T (MTNR1Ac.184+1G>T)] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that MTNR1A mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the MTNR1A variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.