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N Engl J Med. 2013 Nov 21;369(21):2012-2020. doi: 10.1056/NEJMoa1307557. Epub 2013 Nov 6.

Mutant prolactin receptor and familial hyperprolactinemia.

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Academic Endocrine Unit, Radcliffe Department of Medicine (P.J.N., C.M.G., R.V.T.), Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine (C.B.W., P.K.), Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology (M.B., P.A.M.), and the Structural Genomics Consortium (C.B.), University of Oxford, Oxford, and Glasgow Royal Infirmary, Glasgow (S.J.C., M.A., R.S.D.) - all in the United Kingdom.
Contributed equally


Hyperprolactinemia that is not associated with gestation or the puerperium is usually due to tumors in the anterior pituitary gland and occurs occasionally in hereditary multiple endocrine neoplasia syndromes. Here, we report data from three sisters with hyperprolactinemia, two of whom presented with oligomenorrhea and one with infertility. These symptoms were not associated with pituitary tumors or multiple endocrine neoplasia but were due to a heterozygous mutation in the prolactin receptor gene, PRLR, resulting in an amino acid change from histidine to arginine at codon 188 (His188Arg). This substitution disrupted the high-affinity ligand-binding interface of the prolactin receptor, resulting in a loss of downstream signaling by Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). Thus, the familial hyperprolactinemia appears to be due to a germline, loss-of-function mutation in PRLR, resulting in prolactin insensitivity.

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