{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:18:58Z","timestamp":1784557138654,"version":"3.55.0"},"reference-count":61,"publisher":"Bioscientifica","issue":"3","license":[{"start":{"date-parts":[[2023,4,1]],"date-time":"2023-04-01T00:00:00Z","timestamp":1680307200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,4,1]]},"abstract":"<jats:p>\n                    The prolactin receptor (PRLR) signals predominantly through the JAK2-STAT5 pathway regulating multiple physiological functions relating to fertility, lactation, and metabolism. However, the molecular pathology and role of PRLR mutations and signalling are incompletely defined, with progress hampered by a lack of reported disease-associated PRLR variants. To date, two common germline\n                    <jats:italic>PRLR<\/jats:italic>\n                    variants are reported to demonstrate constitutive activity, with one, Ile146Leu, overrepresented in benign breast disease, while a rare activating variant, Asn492Ile, is reported to be associated with an increased incidence of prolactinoma. In contrast, an inactivating germline heterozygous\n                    <jats:italic>PRLR<\/jats:italic>\n                    variant (His188Arg) was reported in a kindred with hyperprolactinaemia, while an inactivating compound heterozygous\n                    <jats:italic>PRLR<\/jats:italic>\n                    variant (Pro269Leu\/Arg171Stop) was identified in an individual with hyperprolactinaemia and agalactia. We hypothesised that additional rare germline\n                    <jats:italic>PRLR<\/jats:italic>\n                    variants, identified from large-scale sequencing projects (ExAC and GnomAD), may be associated with altered\n                    <jats:italic>in vitro<\/jats:italic>\n                    PRLR signalling activity. We therefore evaluated &gt;300 previously uncharacterised non-synonymous, germline\n                    <jats:italic>PRLR<\/jats:italic>\n                    variants and selected 10 variants for\n                    <jats:italic>in vitro<\/jats:italic>\n                    analysis based on protein prediction algorithms, proximity to known functional domains and structural modelling. Five variants, including extracellular and intracellular domain variants, were associated with altered responses when compared to the wild-type receptor. These altered responses included loss- and gain-of-function activities related to STAT5 signalling, Akt and FOXO1 activity, as well as cell viability and apoptosis. These studies provide further insight into PRLR structure\u2013function and indicate that rare germline\n                    <jats:italic>PRLR<\/jats:italic>\n                    variants may have diverse modulating effects on PRLR signalling, although the pathophysiologic relevance of such alterations remains to be defined.\n                  <\/jats:p>","DOI":"10.1530\/jme-22-0164","type":"journal-article","created":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T14:09:40Z","timestamp":1669730980000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":6,"title":["Identification of prolactin receptor variants with diverse effects on receptor signalling"],"prefix":"10.1530","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1361-9174","authenticated-orcid":true,"given":"Caroline M","family":"Gorvin","sequence":"first","affiliation":[{"name":"Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK"},{"name":"Oxford NIHR Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK"},{"name":"Institute of Metabolism and Systems Research (IMSR) & Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, University of Birmingham, Birmingham, UK"},{"name":"Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4414-0278","authenticated-orcid":true,"given":"Paul J","family":"Newey","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK"},{"name":"Division of Molecular & Clinical Medicine (MCM), University of Dundee, Jacqui Wood Cancer Centre, Dundee, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1438-3220","authenticated-orcid":true,"given":"Rajesh V","family":"Thakker","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK"},{"name":"Oxford NIHR Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"Molecular Endocrinology","first-page":"2268","article-title":"Src mediates prolactin-dependent proliferation of T47D and MCF7 cells via the activation of focal adhesion kinase\/ERK1\/2 and phosphatidylinositol 3-kinase pathways","volume":"17","author":"Acosta","year":"2003","unstructured":"Acosta JJMunoz RMGonzalez LSubtil-Rodriguez ADominguez-Caceres MAGarcia-Martinez JMCalcabrini ALazaro-Trueba IMartin-Perez J2003Src mediates prolactin-dependent proliferation of T47D and MCF7 cells via the activation of focal adhesion kinase\/ERK1\/2 and phosphatidylinositol 3-kinase pathways. 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