{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T10:33:07Z","timestamp":1771669987826,"version":"3.50.1"},"reference-count":36,"publisher":"Walter de Gruyter GmbH","issue":"0","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"Abstract<\/jats:title>\n \n Objectives<\/jats:title>\n Central precocious puberty (CPP) develops as a result of early stimulation of the hypothalamic-pituitary-gonadal (HPG) axis. The loss-of-function mutations in the Makorin-ring-finger3 (MKRN3) gene appear to be the most common molecular cause of familial CPP. We aimed to identify MKRN3 gene mutations in our CPP cohort and to investigate the frequency of MKRN3 mutations.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n 102 patients with CPP included. 53 of them had family history of CPP in the first and\/or second-degree relatives. MKRN3 gene was analyzed by next-generation sequencing.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Possible pathogenic variants were found in 2\/53 patients with family history of CPP (3.8%) and 1\/49 patient without family history (2%). A novel heterozygous c.1A>G (p.Met1Val) mutation, a novel heterozygous c.683_684delCA (p.Ser228*) and a previously reported c.482dupC (Ala162Glyfs*) frameshift variations were detected. The two novel variants are predicted to be pathogenic in\u00a0silico analyses.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n In our cohort, possible pathogenic variants in MKRN3 gene were detected in 2.9% of the total cohort, 3.8% of the familial and 2% of the nonfamilial cases, slightly lower than that reported in the literature. Two novel variants detected contribute to the molecular repertoire of MKRN3 defects in CPP. Classical pattern of paternal inheritance has been demonstrated in all three cases. However, the father of the patient 3 did not have history of CPP suggesting that the father inherited this variant from his mother and had phenotype skipping. Therefore, we emphasize that the absence of history of CPP in the father does not exclude the possibility of a MKRN3 mutation.<\/jats:p>\n <\/jats:sec>","DOI":"10.1515\/jpem-2022-0645","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T06:53:26Z","timestamp":1678258406000},"source":"Crossref","is-referenced-by-count":6,"title":["Molecular analysis of MKRN3<\/i> gene in Turkish girls with sporadic and familial idiopathic central precocious puberty"],"prefix":"10.1515","volume":"0","author":[{"given":"Tar\u0131k","family":"K\u0131rkg\u00f6z","sequence":"first","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sare Bet\u00fcl","family":"Kaygusuz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ceren","family":"Alavanda","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Didem","family":"Helvac\u0131o\u011flu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zehra Yava\u015f","family":"Abal\u0131","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00fc\u015fra G\u00fcrp\u0131nar","family":"Tosun","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehmet","family":"Eltan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuba Seven","family":"Menev\u015fe","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tulay","family":"Guran","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmet","family":"Arman","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5172-5402","authenticated-orcid":false,"given":"Serap","family":"Turan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullah","family":"Bereket","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetes , Marmara University School of Medicine , Istanbul , T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2023,3,9]]},"reference":[{"key":"2023030806532309371_j_jpem-2022-0645_ref_001","doi-asserted-by":"crossref","unstructured":"Helvac\u0131o\u011flu, D, Demircio\u011flu Turan, S, G\u00fcran, T, Atay, Z, Da\u011f\u00e7\u0131nar, A, Bezen, D, et al.. 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Central precocious puberty: from genetics to treatment. Best Pract Res Clin Endocrinol Metabol 2018;32:343\u201354. https:\/\/doi.org\/10.1016\/j.beem.2018.05.008.","DOI":"10.1016\/j.beem.2018.05.008"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_007","doi-asserted-by":"crossref","unstructured":"Macedo, DB, Abreu, AP, Reis, AC, Montenegro, LR, Dauber, A, Beneduzzi, D, et al.. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab 2014;99:E1097\u2013103. https:\/\/doi.org\/10.1210\/jc.2013-3126.","DOI":"10.1210\/jc.2013-3126"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_008","doi-asserted-by":"crossref","unstructured":"Simon, D, Ba, I, Mekhail, N, Ecosse, E, Paulsen, A, Zenaty, D, et al.. Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty. 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J Endocr Soc 2019;3:979\u201395. https:\/\/doi.org\/10.1210\/js.2019-00041.","DOI":"10.1210\/js.2019-00041"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_016","doi-asserted-by":"crossref","unstructured":"Bessa, DS, Macedo, DB, Brito, VN, Fran\u00e7a, MM, Montenegro, LR, Cunha-Silva, M, et al.. High frequency of MKRN3 mutations in male central precocious puberty previously classified as idiopathic. Neuroendocrinology 2017;105:17\u201325. https:\/\/doi.org\/10.1159\/000446963.","DOI":"10.1159\/000446963"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_017","doi-asserted-by":"crossref","unstructured":"Aycan, Z, Sava\u015f-Erdeve \u015e, \u00c7etinkaya, S, Kurnaz, E, Keskin, M, Murato\u011flu \u015eahin, N, et al.. Investigation of MKRN3 mutation in patients with familial central precocious puberty. 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A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty. Pediatr Res 2015;78:709\u201311. https:\/\/doi.org\/10.1038\/pr.2015.159.","DOI":"10.1038\/pr.2015.159"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_021","doi-asserted-by":"crossref","unstructured":"Lee, HS, Jin, HS, Shim, YS, Jeong, HR, Kwon, E, Choi, V, et al.. Low frequency of MKRN3 mutations in central precocious puberty among Korean girls. Horm Metab Res 2016;48:118\u201322. https:\/\/doi.org\/10.1055\/s-0035-1548938.","DOI":"10.1055\/s-0035-1548938"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_022","doi-asserted-by":"crossref","unstructured":"Lin, WD, Wang, CH, Tsai, FJ. Genetic screening of the makorin ring finger 3 gene in girls with idiopathic central precocious puberty. Clin Chem Lab Med 2016;54:e93\u20136. https:\/\/doi.org\/10.1515\/cclm-2015-0408.","DOI":"10.1515\/cclm-2015-0408"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_023","doi-asserted-by":"crossref","unstructured":"Ortiz-Cabrera, NV, Riveiro-\u00c1lvarez, R, L\u00f3pez-Mart\u00ednez, M\u00c1, P\u00e9rez-Segura, P, Arag\u00f3n-G\u00f3mez, I, Trujillo-Tiebas, MJ, et al.. Clinical Exome sequencing reveals MKRN3 pathogenic variants in familial and nonfamilial idiopathic central precocious puberty. Horm Res Paediatr 2017;87:88\u201394. https:\/\/doi.org\/10.1159\/000453262.","DOI":"10.1159\/000453262"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_024","doi-asserted-by":"crossref","unstructured":"Grandone, A, Capristo, C, Cirillo, G, Sasso, M, Umano, GR, Mariani, M, et al.. Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty. Horm Res Paediatr 2017;88:194\u2013200. https:\/\/doi.org\/10.1159\/000477441.","DOI":"10.1159\/000477441"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_025","doi-asserted-by":"crossref","unstructured":"Macedo, DB, Fran\u00e7a, MM, Montenegro, LR, Cunha-Silva, M, Best, DS, Abreu, AP, et al.. Central precocious puberty caused by a heterozygous deletion in the MKRN3 promoter region. Neuroendocrinology 2018;107:127\u201332. https:\/\/doi.org\/10.1159\/000490059.","DOI":"10.1159\/000490059"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_026","doi-asserted-by":"crossref","unstructured":"Nishioka, J, Shima, H, Fukami, M, Yatsuga, S, Matsumoto, T, Ushijima, K, et al.. The first Japanese case of central precocious puberty with a novel MKRN3 mutation. Hum Genome Var 2017;4:17017. https:\/\/doi.org\/10.1038\/hgv.2017.17.","DOI":"10.1038\/hgv.2017.17"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_027","doi-asserted-by":"crossref","unstructured":"Suzuki, E, Shima, H, Kagami, M, Soneda, S, Tanaka, T, Yatsuga, S, et al.. Epigenetic defects of MKRN3 are rare in Asian patients with central precocious puberty. Hum Genome Var 2019;6:7. https:\/\/doi.org\/10.1038\/s41439-019-0039-9.","DOI":"10.1038\/s41439-019-0039-9"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_028","doi-asserted-by":"crossref","unstructured":"Fanis, P, Skordis, N, Toumba, M, Papaioannou, N, Makris, A, Kyriakou, A, et al.. Central precocious puberty caused by novel mutations in the promoter and 5\u2019-UTR region of the imprinted MKRN3 gene. Front Endocrinol 2019;10:677. https:\/\/doi.org\/10.3389\/fendo.2019.00677.","DOI":"10.3389\/fendo.2019.00677"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_029","doi-asserted-by":"crossref","unstructured":"Pagani, S, Calcaterra, V, Acquafredda, G, Montalbano, C, Bozzola, E, Ferrara, P, et al.. MKRN3 and KISS1R mutations in precocious and early puberty. Ital J Pediatr 2020;46:39. https:\/\/doi.org\/10.1186\/s13052-020-0808-6.","DOI":"10.1186\/s13052-020-0808-6"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_030","doi-asserted-by":"crossref","unstructured":"Meader, BN, Albano, A, Sekizkardes, H, Delaney, A. Heterozygous deletions in MKRN3 cause central precocious puberty without prader-willi syndrome. 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J Endocr Soc 2022;7:bvac168. https:\/\/doi.org\/10.1210\/jendso\/bvac168.","DOI":"10.1210\/jendso\/bvac168"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_032","doi-asserted-by":"crossref","unstructured":"Stamatiades, GA, Carroll, RS, Kaiser, UB. GnRH-A key regulator of FSH. Endocrinology 2019;160:57\u201367. https:\/\/doi.org\/10.1210\/en.2018-00889.","DOI":"10.1210\/en.2018-00889"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_033","doi-asserted-by":"crossref","unstructured":"Jong, MT, Gray, TA, Ji, Y, Glenn, CC, Saitoh, S, Driscoll, DJ, et al.. A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region. Hum Mol Genet 1999;8:783\u201393. https:\/\/doi.org\/10.1093\/hmg\/8.5.783.","DOI":"10.1093\/hmg\/8.5.783"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_034","doi-asserted-by":"crossref","unstructured":"Nicholls, RD, Saitoh, S, Horsthemke, B. Imprinting in prader-willi and angelman syndromes. Trends Genet 1998;14:194\u2013200. https:\/\/doi.org\/10.1016\/s0168-9525(98)01432-2.","DOI":"10.1016\/S0168-9525(98)01432-2"},{"key":"2023030806532309371_j_jpem-2022-0645_ref_035","doi-asserted-by":"crossref","unstructured":"Simsek, E, Demiral, M, Ceylaner, S, K\u0131rel, B. Two frameshift mutations in MKRN3 in Turkish patients with familial central precocious puberty. 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