HGNC Approved Gene Symbol: PRLR
SNOMEDCT: 237662005, 721601007; ICD10CM: E22.1;
Cytogenetic location: 5p13.2 Genomic coordinates (GRCh38): 5:35,048,756-35,230,487 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.2 | Hyperprolactinemia | 615555 | Autosomal dominant; Autosomal recessive | 3 |
| Multiple fibroadenomas of the breast | 615554 | Autosomal dominant | 3 |
Boutin et al. (1989) isolated human prolactin receptor cDNA clones from hepatoma and breast cancer libraries by use of a rat prolactin (PRL; 176760) receptor cDNA probe. The nucleotide sequence predicted a mature protein of 598 amino acids with a much longer cytoplasmic domain than the rat liver PRL receptor.
Hu et al. (1999) determined the genomic organization of the human PRLR gene. The 5-prime-untranslated region of the PRLR gene contains 2 alternative first exons: E13, the human counterpart of the rat and mouse E13, and a novel human type of alternative first exon termed E1N. The 5-prime-untranslated region also contains a common noncoding exon 2 and part of exon 3, which contains the translation initiation codon. The E13 and E1N exons are within 800 basepairs of each other. These 2 exons are expressed in human breast tissue, breast cancer cells, gonads, and liver. Overall, the transcript containing E13 is prevalent in most tissues. The PRLR gene product is encoded by exons 3-10, of which exon 10 encodes most of the intracellular domain. The E13 and E1N exons are transcribed from alternative promoters PIII and PN, respectively. The PIII promoter contains Sp1 (189906) and C/EBP (see 600749) elements that are identical to those in the rodent promoter and is 81% similar to the region -480/-106 in the rat and mouse. The PN promoter contains putative binding sites for ETS family (see 164720) proteins and a half-site for nuclear receptors.
By somatic cell hybrid analysis and by in situ hybridization, Arden et al. (1989, 1990) demonstrated that the prolactin receptor gene resides in the same chromosomal region as the growth hormone receptor gene (600946), which has been mapped to 5p13-p12.
Gross (2013) mapped the PRLR gene to chromosome 5p13.2 based on an alignment of the PRLR sequence (GenBank AF091870) with the genomic sequence (GRCh37).
There are reasons other than the PRLR gene's proximity to the GHR gene to think that these 2 receptor genes originated from a common precursor. Indeed, growth hormone (GH; 139250) binds to the prolactin receptor, this being the basis of the induction of lactation by growth hormone. Cunningham et al. (1990) demonstrated that zinc greatly increases the affinity of GH for the extracellular binding domain of PRLR, although it is not required for binding of GH to the growth hormone receptor or for binding of prolactin to the prolactin receptor. By mutational analysis, they showed that a cluster of 3 residues (histidine-18, histidine-21, and glutamic acid-174) in GH and histidine-188 in PRLR (conserved in all PRL receptors but not GH receptors) are likely zinc-ion ligands. Cunningham et al. (1990) suggested that their findings may explain the modification of growth hormone action in zinc deficiency, which can lead to growth retardation and hyperprolactinemia. The growth hormone and prolactin receptors are homologous to receptors for members of the cytokine superfamily, such as the receptors for IL2 (147680), IL3 (147740), IL4 (147780), IL6 (147620), IL7 (146660), erythropoietin (133170), and GMCSF (138960).
Perrot-Applanat et al. (1997) examined the function of PRLR isoforms identified in rat that differ in the length of their cytoplasmic domains. Like the known long form (591 amino acids), the Nb2 form, which lacks 198 amino acids of the cytoplasmic domain, is able to transmit a lactogenic signal. In contrast, the short form, which lacks 291 amino acids of the cytoplasmic domain, is inactive. The function of the short form was examined after cotransfection of both the long and short forms. These results show that the short form acts as a dominant-negative inhibitor through the formation of inactive heterodimers, resulting in the inhibition of Janus kinase 2 (147796) activation. The authors concluded that heterodimerization of PRLR can positively or negatively activate PRL transcription.
Using RT-PCR/Southern blot analysis, Ling et al. (2003) demonstrated expression of 4 PRLR mRNA isoforms (L, I, S1a, and S1b) in human subcutaneous abdominal adipose tissue and breast adipose tissue. In addition, they detected L-PRLR and I-PRLR protein expression in human subcutaneous abdominal adipose tissue and breast adipose tissue using immunoblot analysis. PRL reduced the lipoprotein lipase (LPL; 238600) activity in human adipose tissue compared with control. The authors concluded that taken together, these results demonstrated a direct effect of PRL, via functional PRLRs, in reducing the LPL activity in human adipose tissue, and that these results suggested that LPL might also be regulated in this fashion during lactation.
Multiple Fibroadenomas of the Breast
In 74 Caucasian women with multiple fibroadenomas of the breast (MFAB; 615554), who were negative for mutation in the prolactin gene (PRL; 176760), Bogorad et al. (2008) analyzed the PRLR gene and identified heterozygosity for a gain-of-function missense mutation (I146L; 176761.0001) in 4 unrelated patients. In vitro studies demonstrated that the mutation results in a constitutively active receptor, which was confirmed by increased signaling in patient breast tissue.
Newey et al. (2013) questioned the in vivo significance of the I146L variant, noting that it had been reported as a polymorphism (rs72478580) occurring at 2.39% in a European American population in the Exome Variant Server of the NHLBI GO Exome Sequencing Project.
Hyperprolactinemia
In 5 affected members of a 3-generation family segregating autosomal dominant hyperprolactinemia (HPRL; 615555), in which no mutations were found in the MEN1 (613733), AIP (605555), or PRL genes, Newey et al. (2013) identified heterozygosity for a loss-of-function missense mutation in the PRLR gene (H188R; 176761.0002). Functional analysis demonstrated that the mutation, which disrupts the high-affinity ligand-binding interface of the prolactin receptor, results in a loss of downstream signaling by JAK2 (147796) and STAT5 (601511). Kobayashi et al. (2018) stated that this mutation is a his212-to-arg (H212R) substitution.
Harris (2014), Grossmann (2014), and Molitch (2014) questioned the relationship between the H188R (H212R) loss-of-function mutation and the reproductive abnormalities and galactorrhea reported in the family studied by Newey et al. (2013). Newey et al. (2014) proposed the involvement of a hypothetical second receptor mediating peripheral effects of hyperprolactinemia as a possible explanation for the paradoxical occurrence of the loss-of-function mutation in PRLR with hyperprolactinemia and variable reproductive abnormalities, and cited previous studies associating prolactin levels with reproductive function (Bronstein, 2010; Garzia et al., 2004; Li et al., 2013). Newey et al. (2014) also noted that their results showed that the PRLR loss-of-function mutation cosegregated with familial hyperprolactinemia with odds of more than 125 to 1 favoring linkage, and that the mutation was associated with a phenotype similar to that in Prlr-null mice.
In a 35-year-old woman with hyperprolactinemia and agalactia, Kobayashi et al. (2018) sequenced the PRLR gene and identified compound heterozygosity for a nonsense mutation (R171X; 176761.0003) and a missense mutation (P269L; 176761.0004). The proband's parents were each heterozygous for 1 of the mutations, both of which were shown to be loss-of-function variants. The proband's mother, who carried the R171X variant, had no history of menstrual irregularities or infertility and breast-fed each of her 3 children; lactation ceased spontaneously within 3 months after each childbirth. The authors noted that the 3 identified variant receptors (H212R, R171X, and P269L) exhibit similar residual signal-transduction function as well as absence of robust dominant-negative effects, and suggested that other factors that modulate prolactin receptor signaling might explain the difference in phenotype between the 2 reported families with PRLR-associated hyperprolactinemia.
Exclusion Studies
Glasow et al. (2001) examined the presence of PRLR in 41 breast tumors by immunohistochemistry and attempted a correlation of its expression to pathologic grading of the disease (114480). The PRLR immunoreactive score did not correlate to tumor size, histopathologic grading, age, or family history of patients. In both PRLR-positive and -negative breast cancer cells, direct sequencing of the coding sequence of the PRLR gene did not detect any somatic or hereditary gene aberrations. The authors concluded that PRLR mutations do not appear to be common in human breast cancer, suggesting that constitutive activation of PRLR can be excluded as a major cause of mammary tumor genesis.
Ormandy et al. (1997) produced mice carrying a germline null mutation of the Prlr gene by gene targeting in embryonic stem cells. Heterozygous females showed almost complete failure of lactation attributable to greatly reduced mammary gland development after their first, but not subsequent, pregnancies. Homozygous females were sterile owing to a complete failure of embryonic implantation. Moreover, they presented multiple reproductive abnormalities, including irregular cycles, reduced fertilization rates, defective preimplantation embryonic development, and lack of pseudopregnancy. Half of the homozygous males were infertile or showed reduced fertility. Ormandy et al. (1997) concluded that the prolactin receptor is a key regulator of mammalian reproduction and provided the first total ablation model to study further the role of the prolactin receptor and its ligands.
In 4 (5.6%) of 74 Caucasian women with multiple fibroadenomas of the breast (MFAB; 615554), Bogorad et al. (2008) identified heterozygosity for an A-C transversion in exon 6 of the PRLR gene, resulting in an ile146-to-leu (I146L) substitution in the second cytokine receptor homology motif of the PRLR ligand-binding domain. Functional analysis in 3 reconstituted cell models demonstrated constitutive activity with the mutant receptor, as shown by PRL-independent PRLR tyrosine phosphorylation, activation of STAT5 (601511) signaling, transcriptional activity toward a PRL-responsive reporter gene, and cell proliferation and protection from cell death. Constitutive activity of the I146L mutant prolactin receptor in patient breast tissue was supported by increased STAT5 signaling. None of the mutation-positive patients displayed any obvious signs of hyperprolactinemia, although the authors noted that full clinical phenotyping was not performed.
Newey et al. (2013) questioned the in vivo significance of the I146L variant, noting that it had been reported as a polymorphism (rs72478580) occurring at 2.39% in a European American population in the Exome Variant Server of the NHLBI GO Exome Sequencing Project.
This variant is also designated ILE170LEU (I170L), using numbering of the full-length amino acid that includes the signal peptide.
In 5 affected members of a 3-generation family segregating autosomal dominant hyperprolactinemia (HPRL; 615555), Newey et al. (2013) identified heterozygosity for a c.635A-G transition in the PRLR gene, resulting in a his188-to-arg (H188R) substitution at a highly conserved residue in the extracellular domain, located at the interface of the high-affinity binding site-1. The mutation was not found in 3 unaffected members of the family, in 110 ethnically matched controls, or in more than 13,000 alleles from the NHLBI GO Exome Sequencing Project. The proband's 13-year-old prepubertal daughter, who carried the mutation but did not have hyperprolactinemia, was felt to represent age-related penetrance for the disease. Functional analysis in transfected HEK293 cells showed no significant increase in phosphorylated JAK2 (147796) or STAT5A (601511) with the mutant compared to control, indicating that the H188R mutation results in loss of function. Cotransfection with mutant and nonmutant constructs resulted in reduction of CISH reporter expression, consistent with loss of function and a probable dominant-negative effect of the mutant prolactin receptor.
This variant is also designated HIS212ARG (H212R), using numbering of the full-length amino acid that includes the signal peptide.
In a 35-year-old woman with hyperprolactinemia (HPRL; 615555), who experienced complete lack of lactation after each of 2 childbirths, Kobayashi et al. (2018) identified compound heterozygosity for a c.511C-T transition (c.511C-T, NM_000949.6) in exon 6 of the PRLR gene, resulting in an arg171-to-ter (R171X) substitution, and a c.806C-T transition in exon 9, resulting in a pro269-to-leu (P269L; 176761.0004) substitution at the docking site for JAK2 (147796) within the highly conserved box 1 motif of the proline-rich domain. R171X was not listed in public variant databases, whereas P269L had been reported as a SNP with a minor allele frequency of 0.00002. The proband's mother, who was heterozygous for R171X, had no history of menstrual irregularities or infertility and had breast-fed each of her 3 children, but stated that she had been concerned about insufficient production of breast milk and supplemented with synthetic milk; lactation ceased spontaneously within 3 months after each childbirth. The proband's fertile and healthy father was heterozygous for the P269L variant; both parents had normal prolactin levels. Functional analysis in transfected HEK293T cells showed that the R171X mutant was present at significantly lower levels than wildtype PRLR and showed no signal at the cell membrane, whereas the P269L variant was detected in both cytoplasm and the cell membrane and showed an elevated level of expression compared to wildtype PRLR. However, neither mutant phosphorylated STAT5 (601511) in response to prolactin, in contrast to the wildtype prolactin receptor; in addition, neither mutant suppressed STAT5 phosphorylation by the wildtype receptor when equimolar amounts of plasmid were transfected. Quantitative assay revealed that the R171X mutant did not respond to prolactin, whereas the P269L mutant exhibited a blunted response that was suppressed when equimolar amounts of R171X and P269L were present. Only the P269L mutant appeared to have a dominant-negative effect, attenuating the response of the wildtype receptor to prolactin by approximately 20%.
For discussion of the c.806C-T transition (c.806C-T, NM_000949.6) in exon 9 of the PRLR gene, resulting in a pro269-to-leu (P269L) substitution, that was found in compound heterozygous state in a patient with hyperprolactinemia (615555) by Kobayashi et al. (2018), see 176761.0003.
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