Supplementary Material for: Germline Prolactin Receptor Mutation Is Not a Major Cause of Sporadic Prolactinoma in Humans

<b><i>Background/Aims:</i></b> No genetic anomalies specifically predisposing humans to prolactinomas have so far been identified. The prolactin receptor (PRLR) is a good candidate, however, as <i>Prlr</i> knockout mice develop prolactinomas, and a case of familial hyperprolactinemia has been linked to <i>PRLR </i>mutation. The main objective of this study was to detect germline <i>PRLR</i> mutations in patients with sporadic prolactinomas unrelated to <i>AIP</i> or <i>MEN1 </i>mutation. <b><i>Methods:</i></b> We sequenced all <i>PRLR </i>exons and intron-exon junctions on genomic DNA from 88 patients with a median age of 24 years. <b><i>Results:</i></b> We identified 4 <i>PRLR</i> variations (p.Ile76Val, p.Ile146Leu, p.Glu108Lys and p.Glu554Gln) in 16 patients. One patient had the rare variant p.Glu554Gln in the heterozygous state. Another patient had the extremely rare p.Glu108Lys variant described here for the first time. The other 2 variants (p.Ile76Val and p.Ile146Leu) are relatively common in the general population. All these 4 variants have been functionally tested in vitro and have no effect on PRLR expression, localization and signaling after prolactin stimulation. <b><i>Conclusion:</i></b> Inactivating germline variations of <i>PRLR </i>are not associated with sporadic prolactinoma in this series. Nevertheless, somatic disruption of <i>PRLR</i> has not been excluded in this subset of pituitary tumors.



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