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 journalArticle

    52 Citations (Scopus)

    Abstract

    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
    Volume369
    Issue number21
    DOIs
    Publication statusPublished - 21 Nov 2013

    Fingerprint

    Prolactin Receptors
    Hyperprolactinemia
    Multiple Endocrine Neoplasia
    Oligomenorrhea
    STAT5 Transcription Factor
    Janus Kinase 2
    Mutation
    Anterior Pituitary Gland
    Pituitary Neoplasms
    Histidine
    Codon
    Prolactin
    Postpartum Period
    Infertility
    Arginine
    Ligands
    Amino Acids
    Pregnancy
    Genes
    Neoplasms

    Keywords

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

    Cite this

    Newey, P. J., Gorvin, C. M., Cleland, S. J., Willberg, C. B., Bridge, M., Azharuddin, M., ... Thakker, R. V. (2013). Mutant prolactin receptor and familial hyperprolactinemia. New England Journal of Medicine, 369(21), 2012-2020. https://doi.org/10.1056/NEJMoa1307557
    Newey, Paul J. ; Gorvin, Caroline M. ; Cleland, Stephen J. ; Willberg, Christian B. ; Bridge, Marcus ; Azharuddin, Mohammed ; Drummond, Russell S. ; van der Merwe, P. Anton ; Klenerman, Paul ; Bountra, Chas ; Thakker, Rajesh V. / Mutant prolactin receptor and familial hyperprolactinemia. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 21. pp. 2012-2020.
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    abstract = "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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    author = "Newey, {Paul J.} and Gorvin, {Caroline M.} and Cleland, {Stephen J.} and Willberg, {Christian B.} and Marcus Bridge and Mohammed Azharuddin and Drummond, {Russell S.} and {van der Merwe}, {P. Anton} and Paul Klenerman and Chas Bountra and Thakker, {Rajesh V.}",
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    Newey, PJ, Gorvin, CM, Cleland, SJ, Willberg, CB, Bridge, M, Azharuddin, M, Drummond, RS, van der Merwe, PA, Klenerman, P, Bountra, C & Thakker, RV 2013, 'Mutant prolactin receptor and familial hyperprolactinemia', New England Journal of Medicine, vol. 369, no. 21, pp. 2012-2020. https://doi.org/10.1056/NEJMoa1307557

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

    In: New England Journal of Medicine, Vol. 369, No. 21, 21.11.2013, p. 2012-2020.

    Research output: Contribution to journalArticle

    TY - JOUR

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    AU - Newey, Paul J.

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    AU - Willberg, Christian B.

    AU - Bridge, Marcus

    AU - Azharuddin, Mohammed

    AU - Drummond, Russell S.

    AU - van der Merwe, P. Anton

    AU - Klenerman, Paul

    AU - Bountra, Chas

    AU - Thakker, Rajesh V.

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    N2 - 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.

    AB - 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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    KW - Sequence analysis, DNA

    KW - Signal transduction

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    Newey PJ, Gorvin CM, Cleland SJ, Willberg CB, Bridge M, Azharuddin M et al. Mutant prolactin receptor and familial hyperprolactinemia. New England Journal of Medicine. 2013 Nov 21;369(21):2012-2020. https://doi.org/10.1056/NEJMoa1307557