Results of targeted sequencing of the PRL, PRLR, PRLHR genes in young women with non-tumor hyperprolactinemia

Aim. To study the spectrum of variants in the PRL, PRLR, PRLHR genes in women of reproductive age with non-tumor hyperprolactinemia. Material and methods. In women with non-tumor hyperprolactinemia (n = 15), targeted high-throughput sequencing of the PRL, PRLR, and PRLHR genes was performed. The target panel of genes included coding regions and adjacent splicing sites. Results. When analyzing the PRL, PRLR, PRLHR genes, a number of rare and common variants were identified. The common variant rs1205955 was found in the PRL gene (MAF А = 0.279). For the PRLR gene, a rare variant rs185353023 was identified in the 3’UTR (MAF А/С = 0.003) and 12 common variants. For the PRLHR gene, 10 common variants have been identified. The maximum number of variants was localized in the 3’UTR region and introns. Conclusions. For the first time in Russia, targeted high-throughput sequencing of the PRL, PRLR, PRLHR genes was performed, the results of which did not reveal obvious pathological variants in the studied genes in women with high prolactin content of non-tumor origin. The discovered polymorphism in these genes makes it possible to further study its association with impaired function of the prolactin link of hormonal regulation.

1. Bernard V., Young J., Binart N. Prolactin – a pleiotropic factor in health and disease. Nat. Rev. Endocrinol. 2019;15(6):356. doi: 10.1038/s41574-019-0194-6

2. Bernard V., Young J., Chanson P., Binart N. New insights in prolactin: pathological implications. Nat. Rev. Endocrinol. 2015;11(5):265–275. doi: 10.1038/nrendo.2015.36

3. Mel’nichenko G.A., Dzeranova L.K., Pigarova E.A., Vorotnikova S.Yu., Rozhinskaya L.Ya., Dedov I.I. Federal clinical guidelines on the clinic, diagnosis, differential diagnosis and treatment of hyperprolactinemia. Problemy endocrinologii = Problems of Endocrinology. 2013;59(6):19–26. [In Russian].

4. Rymar O.D., Mikitinskaya A.K., Maksimov V.N., Mustafina S.V. The role of the genetic factors in the etiology of autoimmune thyroid disease. Sibirskiy meditsinskiy zhurnal (Tomsk) = Siberian Medical Journal (Tomsk). 2011;26(4-2):35–40. [In Russian].

5. Nikitin Yu.P., Rymar O.D., Maksimov V.N., Simonova G.I., Mustafina S.V., Shcherbakova L.V., Zankina M.A., Chernova N.N., Voevoda M.I. Association of PTPN22 haplotypes with hashimotos thyroiditis in population of Novosibirsk. Klinicheskaya i eksperimental’naya tireoidologiya = Clinical and Experimental Thyroidology. 2009;5(1):47–52. [In Russian].

6. Voevoda M.I., Ivanova A.A., Shahtshnejder E.V., Ovsyannikova A.K., Mihailova S.V., Astrakova K.S., Voevoda S.M., Rymar O.D. Molecular genetics of maturity-onset diabetes of the young. Terapevticheskiy arkhiv = Therapeutic Archive. 2016;88(4):117–124. [In Russian]. doi: 10.17116/terarkh2016884117-124

7. Birla S., Khadgawat R., Jyotsna V.P., Jain V., Garg M.K., Bhalla A.S., Sharma A. Identification of novel PROP1 and POU1F1 mutations in patients with combined pituitary hormone deficiency. Horm. Metab. Res. 2016;48(12):822–827. doi: 10.1055/s-0042-117112

8. Reynaud R., Gueydan M., Saveanu A., Vallette-Kasic S., Enjalbert A., Brue T., Barlier A. Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. J. Clin. Endocrinol. Metab. 2006;91(9):3329–3336. doi: 10.1210/jc.2005-2173

9. Rainbow L.A., Rees S.A., Shaikh M.G., Shaw N.J., Cole T., Barrett T.G., Kirk J.M. Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia. Clin. Endocrinol. (Oxf). 2005;62(2):163–168. doi: 10.1111/j.1365-2265.2004.02189.x

10. Carlomagno Y., Salerno M., Vivenza D., Capalbo D., Godi M., Mellone S., Tiradani L., Corneli G., Momigliano-Richiardi P., Bona G., Giordano M. A novel recessive splicing mutation in the POU1F1 gene causing combined pituitary hormone deficiency. J. Endocrinol. Invest. 2009;32(8):653–658. doi: 10.1007/bf03345736

11. Sambrook J., Russell D.W. Purification of nucleic acids by extraction with phenol:chloroform. CSH Protoc. 2006;2006(1):pdb.prot4455. doi: 10.1101/pdb.prot4455

12. Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Grody W.W., Hegde M., Lyon E., … ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. doi: 10.1038/gim.2015.30

13. Stenson P.D., Ball E.V., Mort M.E., Phillips A.D., Shiel J.A., Thomas N.S., Abeysinghe S.S., Krawczak M., Cooper D.N. Human gene mutation database (HGMD®): 2003 update. Human Mutation. 2003;21(6): 577–581. doi: 10.1002/HUMU.10212

14. Landrum M.J., Lee J.M., Benson M., Brown G.R., Chao C., Chitipiralla S., Gu B., Hart J., Hoffman D., Jang W., … Maglott D.R. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic. Acids. Res. 2018;46(D1):1062–1067. doi: 10.1093/nar/gkx1153

15. Ben-Jonathan N., LaPensee C.R., LaPensee E.W. What can we learn from rodents about prolactin in humans? Endocr. Rev. 2008;29(1):1–41. doi: 10.1210/er.2007-0017

16. Hernández-Bello J., Palafox-Sanchez C.A., García-Arellano S., Reyes-Castillo Z., Pereira-Suárez A.L., Parra-Rojas I., Navarro-Zarza J.E., de la Cruz-Mosso U., Torres-Carrillo N.M., Muñoz-Valle J.F. Association of extrapituitary prolactin promoter polymorphism with disease susceptibility and anti-RNP antibodies in Mexican patients with systemic lupus erythematosus. Arch. Med. Sci. 2018;14(5):1025–1032. doi: 10.5114/aoms.2016.62138

17. Ivanova S.A., Osmanova D.Z., Boiko A.S., Pozhidaev I.V., Freidin M.B., Fedorenko O.Y., Semke A.V., Bokhan N.A., Kornetova E.G., Rakhmazova L.D., Wilffert B., Loonen A.J. Schizophr Prolactin gene polymorphism (–1149 G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics. Schizophr. Res. 2017;182:110–114. doi: 10.1016/j.schres.2016.10.029

18. Abramicheva P.A., Smirnova O.V. Prolactin receptor isoforms as the basis of tissue-specific action of prolactin in the norm and pathology. Biochemistry. Mosc. 2019;84(4):329–345. doi: 10.1134/S0006297919040011

19. Hu Z., Zhuang L., Meng J., Tsai-Morris C., Dufau M.L. Complex 5’ genomic structure of the human prolactin receptor: multiple alternative exons 1 and promoter utilization. Endocrinology. 2002;143(6):2139–2142.

20. Chang S., Copperman A.B. New insights into human prolactin pathophysiology: genomics and beyond. Curr. Opin. Obstet. Gynecol. 2019;31(4):207–211. doi: 10.1097/GCO.0000000000000545

21. Kavarthapu R., Dufau M.L. Essential role of endogenous prolactin and CDK7 in estrogen-induced upregulation of the prolactin receptor in breast cancer cells. Oncotarget. 2017;8(16):27353–27363. doi: 10.18632/oncotarget.16040

22. Newey P.J., Gorvin C.M., Cleland S.J., Willberg C.B., Bridge M., Azharuddin M., Drummond R.S., van der Merwe P.A., Klenerman P., Bountra C., Thakker R.V. Mutant prolactin receptor and familial hyperprolactinemia. N. Engl. J. Med. 2013;369(21):2012–2020. doi: 10.1056/NEJMoa1307557

23. Kobayashi T., Usui H., Tanaka H., Shozu M. Variant Pprolactin receptor in agalactia and hyperprolactinemia. N. Engl. J. Med. 2018;379(23):2230–2236. doi: 10.1056/NEJMoa1805171

24. Abe T., Koga N., Tomita M., Tonoike T., Kushima M., Takahashi K., Sano Y., Taniyama M. Cellular localization of prolactin-releasing peptide receptors in the human pituitary. Acta Neuropathologica. 2003;106(5):495–500. doi: 10.1007/s00401-003-0753-7

25. Tachibana T., Sakamoto T. Functions of two distinct “prolactin-releasing peptides” evolved from a common ancestral gene. Front. Endocrinol. (Lausanne). 2014;5:170. doi: 10.3389/fendo.2014.00170

26. Gu W., Geddes B.J., Zhang C.P., Foley K.P., Stricker-Krongrad A. The prolactin-releasing peptide receptor (GPR10) regulates body weight homeostasis in mice. J. Mol. Neurosci. 2004;22(1–2):93–103. doi: 10.1385/JMN:22:1-2:93

27. Grattan D.R. 60 years of neuroendocrinology: The hypothalamo-prolactin axis. J. Endocrinol. 2015;226(2):101–122. doi: 10.1530/JOE-15-0213