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Caroline M Gorvin, Paul J Newey, and Rajesh V Thakker

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 PRLR 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 PRLR variant (His188Arg) was reported in a kindred with hyperprolactinaemia, while an inactivating compound heterozygous PRLR variant (Pro269Leu/Arg171Stop) was identified in an individual with hyperprolactinaemia and agalactia. We hypothesised that additional rare germline PRLR variants, identified from large-scale sequencing projects (ExAC and GnomAD), may be associated with altered in vitro PRLR signalling activity. We therefore evaluated >300 previously uncharacterised non-synonymous, germline PRLR variants and selected 10 variants for in vitro 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–function and indicate that rare germline PRLR variants may have diverse modulating effects on PRLR signalling, although the pathophysiologic relevance of such alterations remains to be defined.

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Ashley A Able, Allison J Richard, and Jacqueline M Stephens

the JAK-STAT5 pathway and modulates STAT5 activation . Blood 89 3148 – 3154 . 9129017 Moreno-Navarrete JM Moreno M Vidal M Ortega F Serrano M Xifra G Ricart W Fernández-Real JM 2015a Deleted in breast cancer 1 plays a functional role in

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J M Fleming, E Ginsburg, C W McAndrew, C D Heger, L Cheston, J Rodriguez-Canales, B K Vonderhaar, and P Goldsmith

of the JAK/STAT5 signaling pathway ( Vonderhaar & Ziska 1989 ), and has been shown to activate other common proliferative signal transduction pathways in breast epithelial cells (AKT, ERK1/2) ( Brisken & O'Malley 2010 , LaPensee & Ben-Jonathan 2010

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Drake Hechter, Brett Vahkal, Tiana Tiede, and Sara V Good

et al. 2017 , 2018 , Kocan et al. 2018 ). INSL5 binding to RXFP4 can increase phosphorylation of ERK1/2, p38MAPK, Akt-Ser473, Akt-Thr308, JAK/STAT5 ( Li et al. 2020 ), and S6 ribosomal protein (S6RP) ( Ang et al. 2017 , 2018 , Kocan et al