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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 publication

DOI

10.1056/NEJMoa1307557

Type

Journal article

Journal

N Engl J Med

Publication Date

21/11/2013

Volume

369

Pages

2012 - 2020

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