Mutant prolactin receptor and familial hyperprolactinemia

Paul J. Newey, Caroline M. Gorvin, Stephen J. Cleland, Christian B. Willberg, Marcus Bridge, Mohammed Azharuddin, Russell S. Drummond, P. Anton van der Merwe, Paul Klenerman, Chas Bountra, Rajesh V. Thakker (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    93 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)2012-2020
    Number of pages9
    JournalNew England Journal of Medicine
    Issue number21
    Publication statusPublished - 21 Nov 2013


    • Adult
    • Female
    • Germ-line mutation
    • Humans
    • Hyperprolactinemia
    • Janus kinase 2
    • Male
    • Pedigree
    • Protein conformation
    • Receptors, Prolactin
    • STAT5 transcription factor
    • Sequence analysis, DNA
    • Signal transduction


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