{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:54:36Z","timestamp":1791287676335,"version":"4.1.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2016,1,13]],"date-time":"2016-01-13T00:00:00Z","timestamp":1452643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,6,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>The cyclic adenosine monophosphate (cAMP) intracellular signaling pathway mediates the physiological effects of several hormones and neurotransmitters, acting by the activation of G-protein coupled receptors (GPCRs) and several downstream intracellular effectors, including the heterotrimeric stimulatory G-protein (Gs), the cAMP-dependent protein kinase A (PKA), and cAMP-specific phosphodiesterases (PDEs). Defective G-protein\u2013mediated signaling has been associated with an increasing number of disorders, including Albright hereditary osteodistrophy (AHO) and pseudohypoparathyroidism (PHP), a heterogeneous group of rare genetic metabolic disorders resulting from molecular defects at the GNAS locus. Moreover, mutations in PRKAR1A and PDE4D genes have been recently detected in patients with acrodysostosis (ACRDYS), showing a skeletal and endocrinological phenotype partially overlapping with AHO\/PHP. Despite the high detection rate of molecular defects by currently available molecular approaches, about 30% of AHO\/PHP patients still lack a molecular diagnosis, hence the need to screen patients negative for GNAS epi\/genetic defects also for chromosomal regions and genes associated with diseases that undergo differential diagnosis with PHP. According to the growing knowledge on Gs\u03b1-cAMP signaling-linked disorders, we investigated our series of patients (n\u2009=\u200981) with a clinical diagnosis of PHP\/AHO but negative for GNAS anomalies for the presence of novel genetic variants at PRKAR1A and PDE4D genes. Our work allowed the detection of 8 novel missense variants affecting genes so far associated with ACRDYS in 9 patients. Our data further confirm the molecular and clinical overlap among these disorders. We present the data collected from a large series of patients and a brief review of the literature in order to compare our findings with already published data; to look for PRKAR1A\/PDE4D mutation spectrum, recurrent mutations, and mutation hot spots; and to identify specific clinical features associated with ACRDYS that deserve surveillance during follow-up. \u00a9 2016 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2785","type":"journal-article","created":{"date-parts":[[2016,1,14]],"date-time":"2016-01-14T03:35:38Z","timestamp":1452742538000},"page":"1215-1224","source":"Crossref","is-referenced-by-count":55,"title":["Screening of <i>PRKAR1A<\/i> and <i>PDE4D<\/i> in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and\/or Pseudohypoparathyroidism"],"prefix":"10.1093","volume":"31","author":[{"given":"Francesca Marta","family":"Elli","sequence":"first","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Bordogna","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"de Sanctis","sequence":"additional","affiliation":[{"name":"Department of Public Health and PediatricsUniversity of Turin and Regina Margherita Children's HospitalTurinItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Giachero","sequence":"additional","affiliation":[{"name":"Department of Public Health and PediatricsUniversity of Turin and Regina Margherita Children's HospitalTurinItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Verrua","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Segni","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Child NeuropsychiatrySapienza UniversityRomeItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Mazzanti","sequence":"additional","affiliation":[{"name":"Pediatrics Endocrinology and Rare Diseases, Pediatrics Unit, AOU S. Orsola-MalpighiUniversity of BolognaBolognaItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Boldrin","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alma","family":"Toromanovic","sequence":"additional","affiliation":[{"name":"Department of PediatricsUniversity Clinical Center TuzlaTuzlaBosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Spada","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Mantovani","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,1,13]]},"reference":[{"issue":"3)","key":"2024021014183306400_jbmr2785-bib-0001","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1210\/edrv-13-3-536","article-title":"Receptor-effector coupling by G proteins: implications for normal and abnormal signal transduction","volume":"13","author":"Spiegel","year":"1992","journal-title":"Endocr Rev"},{"key":"2024021014183306400_jbmr2785-bib-0002","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev.med.55.091902.103843","article-title":"Inherited diseases involving g proteins and g protein-coupled receptors","volume":"55","author":"Spiegel","year":"2004","journal-title":"Annu Rev Med"},{"key":"2024021014183306400_jbmr2785-bib-0003","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S1040-7952(97)80019-5","article-title":"Structure, function, and regulation of human cAMP-dependent protein kinases","volume":"31","author":"Task\u00e9n","year":"1997","journal-title":"Adv Second Messenger Phosphoprotein Res"},{"key":"2024021014183306400_jbmr2785-bib-0004","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1146\/annurev.bi.59.070190.004543","article-title":"cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes","volume":"59","author":"Taylor","year":"1990","journal-title":"Annu Rev Biochem"},{"issue":"12)","key":"2024021014183306400_jbmr2785-bib-0005","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/ncpendmet0324","article-title":"Mechanisms of disease: mutations of G proteins and G-protein-coupled receptors in endocrine diseases","volume":"2","author":"Lania","year":"2006","journal-title":"Nat Clin Pract Endocrinol Metab"},{"issue":"10)","key":"2024021014183306400_jbmr2785-bib-0006","doi-asserted-by":"crossref","first-page":"3020","DOI":"10.1210\/jc.2011-1048","article-title":"Clinical review: pseudohypoparathyroidism: diagnosis and treatment","volume":"96","author":"Mantovani","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2024021014183306400_jbmr2785-bib-0007","first-page":"327","author":"Mantovani"},{"issue":"3)","key":"2024021014183306400_jbmr2785-bib-0008","doi-asserted-by":"crossref","first-page":"E508","DOI":"10.1210\/jc.2013-3086","article-title":"Quantitative analysis of methylation defects and correlation with clinical characteristics in patients with pseudohypoparathyroidism type I and GNAS epigenetic alterations","volume":"99","author":"Elli","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"1)","key":"2024021014183306400_jbmr2785-bib-0009","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2214\/ajr.128.1.95","article-title":"Acrodysostosis coinciding with pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism","volume":"128","author":"Ablow","year":"1977","journal-title":"AJR Am J Roentgenol"},{"issue":"23)","key":"2024021014183306400_jbmr2785-bib-0010","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1056\/NEJMoa1012717","article-title":"Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance","volume":"364","author":"Linglart","year":"2011","journal-title":"N Engl J Med"},{"issue":"4)","key":"2024021014183306400_jbmr2785-bib-0011","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.ajhg.2012.03.003","article-title":"Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis","volume":"90","author":"Michot","year":"2012","journal-title":"Am J Hum Genet"},{"key":"2024021014183306400_jbmr2785-bib-0012","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.ajhg.2012.03.004","article-title":"Exome sequencing identifies PDE4D mutations in acrodysostosis","volume":"90","author":"Lee","year":"2012","journal-title":"Am J Hum Genet"},{"issue":"9)","key":"2024021014183306400_jbmr2785-bib-0013","doi-asserted-by":"crossref","first-page":"E1808","DOI":"10.1210\/jc.2012-1369","article-title":"PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance","volume":"97","author":"Nagasaki","year":"2012","journal-title":"Clin Endocrinol Metab"},{"issue":"12)","key":"2024021014183306400_jbmr2785-bib-0014","doi-asserted-by":"crossref","first-page":"E2328","DOI":"10.1210\/jc.2012-2326","article-title":"PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance","volume":"97","author":"Linglart","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"1)","key":"2024021014183306400_jbmr2785-bib-0015","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/humu.22222","article-title":"Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis","volume":"34","author":"Lynch","year":"2013","journal-title":"Hum Mutat"},{"issue":"6)","key":"2024021014183306400_jbmr2785-bib-0016","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1111\/cge.12106","article-title":"Novel mutations of the PRKAR1A gene in patients with acrodysostosis","volume":"84","author":"Muhn","year":"2013","journal-title":"Clin Genet"},{"issue":"1)","key":"2024021014183306400_jbmr2785-bib-0017","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1136\/jmedgenet-2013-101937","article-title":"Different mutations in PDE4D associated with developmental disorders with mirror phenotypes","volume":"51","author":"Lindstrand","year":"2014","journal-title":"J Med Genet"},{"issue":"11)","key":"2024021014183306400_jbmr2785-bib-0018","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1016\/j.cellsig.2014.07.025","article-title":"Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis","volume":"26","author":"Kaname","year":"2014","journal-title":"Cell Signal"},{"issue":"8)","key":"2024021014183306400_jbmr2785-bib-0019","doi-asserted-by":"crossref","first-page":"13267","DOI":"10.3390\/ijms150813267","article-title":"The first mutation identified in a Chinese acrodysostosis patient confirms a p.G289E variation of PRKAR1A causes acrodysostosis","volume":"15","author":"Li","year":"2014","journal-title":"Int J Mol Sci"},{"issue":"10)","key":"2024021014183306400_jbmr2785-bib-0020","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1002\/ajmg.a.36669","article-title":"Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2","volume":"164","author":"Mitsui","year":"2014","journal-title":"Am J Med Genet A"},{"key":"2024021014183306400_jbmr2785-bib-0021","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/bonekey.2012.225","article-title":"Clauser","volume":"1","author":"Silve","year":"2012","journal-title":"Acrodysostosis syndromes. Bonekey Rep"},{"issue":"3)","key":"2024021014183306400_jbmr2785-bib-0022","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/humu.22265","article-title":"Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations","volume":"34","author":"Elli","year":"2013","journal-title":"Hum Mutat"},{"issue":"3)","key":"2024021014183306400_jbmr2785-bib-0023","doi-asserted-by":"crossref","first-page":"E508","DOI":"10.1210\/jc.2013-3086","article-title":"Quantitative analysis of methylation defects and correlation with clinical characteristics in patients with pseudohypoparathyroidism type I and GNAS epigenetic alterations","volume":"99","author":"Elli","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"4)","key":"2024021014183306400_jbmr2785-bib-0024","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/humu.21178","article-title":"Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update","volume":"31","author":"Horvath","year":"2010","journal-title":"Hum Mutat"},{"key":"2024021014183306400_jbmr2785-bib-0025","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1042\/bj3280539","article-title":"Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene","author":"Bolger","year":"1997","journal-title":"Biochem J"},{"key":"2024021014183306400_jbmr2785-bib-0026","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1042\/BJ20050030","article-title":"Splice variants of the cyclic nucleotide phosphodiesterase PDE4D are differentially expressed and regulated in rat tissue","author":"Richter","year":"2005","journal-title":"Biochem J"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.2785","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/6\/1215\/56649375\/jbmr2785.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/6\/1215\/56649375\/jbmr2785.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:55:45Z","timestamp":1710341745000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/31\/6\/1215-1224\/7605180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,13]]},"references-count":26,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2016,1,13]]},"published-print":{"date-parts":[[2016,6,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.2785","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,6,1]]},"published":{"date-parts":[[2016,1,13]]}}}