The Key Roles of Makorin RING Finger Protein 3 (MKRN3) During
the Development of Pubertal Initiation and Central Precocious
Puberty (CPP)

doi:10.2174/1566524022666220624105430
摘要

青春期始于下丘脑中促性腺激素释放激素（GnRH）的持续和不断增长的脉动分泌，然后是下丘脑-垂体-性腺（HPG）轴的激活。许多因素涉及青春期启动，其异常可能来自这些调节器的功能障碍。Makorin RING指蛋白3（MKRN3）抑制GnRH的分泌，在青春期发病过程中起着不可或缺的作用，MKRN3突变是中枢性性早熟（CPP）最常见的遗传原因。最近，越来越多的研究揭示了MKRN3在青春期启动和CPP发生的功能机制。本文主要综述了MKRN3在青春期发病中的作用及其基础机制的研究进展，有助于进一步了解青春期发病的确切机制和CPP的发病机制。
关键词: 马科林无名指蛋白3，MKRN3，青春期开始，中枢性性早熟，CPP，GnRH
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[1]
Tena-Sempere M. Keeping puberty on time: Novel signals and mechanisms involved. Curr Top Dev Biol  2013; 105: 299-329.
 [http://dx.doi.org/10.1016/B978-0-12-396968-2.00011-7] [PMID: 23962847]

[2]
Bradley SH, Lawrence N, Steele C, Mohamed Z. Precocious puberty. BMJ  2020; 368: l6597.
 [http://dx.doi.org/10.1136/bmj.l6597] [PMID: 31932347]

[3]
Ojeda SR, Lomniczi A, Mastronardi C, et al. Minireview: The neuroendocrine regulation of puberty: Is the time ripe for a systems biology approach? Endocrinology  2006; 147(3): 1166-74.
 [http://dx.doi.org/10.1210/en.2005-1136] [PMID: 16373420]

[4]
Abreu AP, Kaiser UB. Pubertal development and regulation. Lancet Diabetes Endocrinol  2016; 4(3): 254-64.
 [http://dx.doi.org/10.1016/S2213-8587(15)00418-0] [PMID: 26852256]

[5]
Chirico V, Lacquaniti A, Salpietro V, Buemi M, Salpietro C, Arrigo T. Central precocious puberty: From physio-pathological mechanisms to treatment. J Biol Regul Homeost Agents  2014; 28(3): 367-75.
 [PMID: 25316125]

[6]
Ojeda SR, Lomniczi A, Sandau U, Matagne V. New concepts on the control of the onset of puberty. Endocr Dev  2010; 17: 44-51.
 [http://dx.doi.org/10.1159/000262527] [PMID: 19955755]

[7]
Howard SR, Dunkel L. Delayed puberty-phenotypic diversity, molecular genetic mechanisms, and recent discoveries. Endocr Rev  2019; 40(5): 1285-317.
 [http://dx.doi.org/10.1210/er.2018-00248] [PMID: 31220230]

[8]
Latronico AC, Brito VN, Carel JC. Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol  2016; 4(3): 265-74.
 [http://dx.doi.org/10.1016/S2213-8587(15)00380-0] [PMID: 26852255]

[9]
Partsch CJ, Sippell WG. Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Hum Reprod Update  2001; 7(3): 292-302.
 [http://dx.doi.org/10.1093/humupd/7.3.292] [PMID: 11392376]

[10]
Nabhan ZM, Mieszczak J, Eugster EA. Combined central precocious puberty and primary gonadal failure after treatment of childhood malignancy in two boys: A diagnostic and therapeutic conundrum. J Pediatr  2010; 157(3): 507-9.
 [http://dx.doi.org/10.1016/j.jpeds.2010.04.039] [PMID: 20542283]

[11]
Kiess W, Hoppmann J, Gesing J, et al. Puberty - genes, environment and clinical issues. J Pediatr Endocrinol Metab  2016; 29(11): 1229-31.
 [http://dx.doi.org/10.1515/jpem-2016-0394] [PMID: 27771625]

[12]
Jong MT, Gray TA, Ji Y, 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(5): 783-93.
 [http://dx.doi.org/10.1093/hmg/8.5.783] [PMID: 10196367]

[13]
Roberts SA, Kaiser UB. Genetics in endocrinology: Genetic etiologies of central precocious puberty and the role of imprinted genes. Eur J Endocrinol  2020; 183(4): R107-17.
 [http://dx.doi.org/10.1530/EJE-20-0103] [PMID: 32698138]

[14]
Böhne A, Darras A, D’Cotta H, Baroiller JF, Galiana-Arnoux D, Volff JN. The vertebrate makorin ubiquitin ligase gene family has been shaped by large-scale duplication and retroposition from an ancestral gonad-specific, maternal-effect gene. BMC Genomics  2010; 11(1): 721.
 [http://dx.doi.org/10.1186/1471-2164-11-721] [PMID: 21172006]

[15]
Abreu AP, Dauber A, Macedo DB, et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med  2013; 368(26): 2467-75.
 [http://dx.doi.org/10.1056/NEJMoa1302160] [PMID: 23738509]

[16]
Busch AS, Hagen CP, Almstrup K, Juul A. Circulating MKRN3 levels decline during puberty in healthy boys. J Clin Endocrinol Metab  2016; 101(6): 2588-93.
 [http://dx.doi.org/10.1210/jc.2016-1488] [PMID: 27057785]

[17]
Hughes IA. Releasing the brake on puberty. N Engl J Med  2013; 368(26): 2513-5.
 [http://dx.doi.org/10.1056/NEJMe1306743] [PMID: 23738512]

[18]
Varimo T, Hero M, Känsäkoski J, Vaaralahti K, Matikainen N, Raivio T. Circulating makorin ring-finger protein-3 (MKRN3) levels in healthy men and in men with hypogonadotropic hypogonadism. Clin Endocrinol  2016; 84(4): 638.
 [http://dx.doi.org/10.1111/cen.13027] [PMID: 26970436]

[19]
Maione L, Naulé L, Kaiser UB. Makorin RING finger protein 3 and central precocious puberty. Curr Opin Endocr Metab Res  2020; 14: 152-9.
 [http://dx.doi.org/10.1016/j.coemr.2020.08.003] [PMID: 32984644]

[20]
Naulé L, Kaiser UB. Evolutionary conservation of MKRN3 and other makorins and their roles in puberty initiation and endocrine functions. Semin Reprod Med  2019; 37(4): 166-73.
 [http://dx.doi.org/10.1055/s-0039-3400965] [PMID: 31972861]

[21]
Bulcao Macedo D, Nahime Brito V, Latronico AC. New causes of central precocious puberty: The role of genetic factors. Neuroendocrinology  2014; 100(1): 1-8.
 [http://dx.doi.org/10.1159/000366282] [PMID: 25116033]

[22]
Ramos CO, Macedo DB, Canton APM, et al. Outcomes of patients with central precocious puberty due to loss-of-function mutations in the MKRN3 gene after treatment with gonadotropin-releasing hormone analog. Neuroendocrinology  2020; 110(7-8): 705-13.
 [http://dx.doi.org/10.1159/000504446] [PMID: 31671431]

[23]
Kota AS, Ejaz S. Precocious puberty. In: StatPearls. Treasure Island (FL): StatPearls Publishing 2021.

[24]
Li C, Lu W, Yang L, et al. MKRN3 regulates the epigenetic switch of mammalian puberty via  ubiquitination of MBD3. Natl Sci Rev  2020; 7(3): 671-85.
 [http://dx.doi.org/10.1093/nsr/nwaa023] [PMID: 34692086]

[25]
Li C, Han T, Li Q, et al. MKRN3-mediated ubiquitination of Poly(A)-binding proteins modulates the stability and translation of GNRH1 mRNA in mammalian puberty. Nucleic Acids Res  2021; 49(7): 3796-813.
 [http://dx.doi.org/10.1093/nar/gkab155] [PMID: 33744966]

[26]
Nagae M, Uenoyama Y, Okamoto S, et al. Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator. Proc Natl Acad Sci USA  2021; 118(5): e2009156118.
 [http://dx.doi.org/10.1073/pnas.2009156118] [PMID: 33500349]

[27]
Heras V, Sangiao-Alvarellos S, Manfredi-Lozano M, et al. Hypothalamic miR-30 regulates puberty onset via  repression of the puberty-suppressing factor, Mkrn3. PLoS Biol  2019; 17(11): e3000532.
 [http://dx.doi.org/10.1371/journal.pbio.3000532] [PMID: 31697675]

[28]
Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev  2009; 23(7): 781-3.
 [http://dx.doi.org/10.1101/gad.1787609] [PMID: 19339683]

[29]
Stefanska B, MacEwan DJ. Epigenetics and pharmacology. Br J Pharmacol  2015; 172(11): 2701-4.
 [http://dx.doi.org/10.1111/bph.13136] [PMID: 25966315]

[30]
Ho DH, Burggren WW. Epigenetics and transgenerational transfer: A physiological perspective. J Exp Biol  2010; 213(1): 3-16.
 [http://dx.doi.org/10.1242/jeb.019752] [PMID: 20008356]

[31]
Burris HH, Baccarelli AA. Environmental epigenetics: From novelty to scientific discipline. J Appl Toxicol  2014; 34(2): 113-6.
 [http://dx.doi.org/10.1002/jat.2904] [PMID: 23836446]

[32]
Jenuwein T, Allis CD. Translating the histone code. Science  2001; 293(5532): 1074-80.
 [http://dx.doi.org/10.1126/science.1063127] [PMID: 11498575]

[33]
Hu H, Sun SC. Ubiquitin signaling in immune responses. Cell Res  2016; 26(4): 457-83.
 [http://dx.doi.org/10.1038/cr.2016.40] [PMID: 27012466]

[34]
Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem  1998; 67(1): 425-79.
 [http://dx.doi.org/10.1146/annurev.biochem.67.1.425] [PMID: 9759494]

[35]
Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem  2009; 78(1): 399-434.
 [http://dx.doi.org/10.1146/annurev.biochem.78.101807.093809] [PMID: 19489725]

[36]
Margolin DH, Kousi M, Chan YM, et al. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N Engl J Med  2013; 368(21): 1992-2003.
 [http://dx.doi.org/10.1056/NEJMoa1215993] [PMID: 23656588]

[37]
Zhao X, Su X, Cao L, et al. OTUD4: A potential prognosis biomarker for multiple human cancers. Cancer Manag Res  2020; 12: 1503-12.
 [http://dx.doi.org/10.2147/CMAR.S233028] [PMID: 32184655]

[38]
Yellapragada V, Liu X, Lund C, et al. MKRN3 interacts with several proteins implicated in puberty timing but does not influence GNRH1 expression. Front Endocrinol  2019; 10: 48.
 [http://dx.doi.org/10.3389/fendo.2019.00048] [PMID: 30800097]

[39]
Han SK, Gottsch ML, Lee KJ, et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci  2005; 25(49): 11349-56.
 [http://dx.doi.org/10.1523/JNEUROSCI.3328-05.2005] [PMID: 16339030]

[40]
Rometo AM, Krajewski SJ, Voytko ML, Rance NE. Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab  2007; 92(7): 2744-50.
 [http://dx.doi.org/10.1210/jc.2007-0553] [PMID: 17488799]

[41]
Navarro VM, Fernández-Fernández R, Castellano JM, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol  2004; 561(Pt 2): 379-86.
 [http://dx.doi.org/10.1113/jphysiol.2004.072298] [PMID: 15486019]

[42]
Terasawa E, Guerriero KA, Plant TM. Kisspeptin and puberty in mammals. Adv Exp Med Biol  2013; 784: 253-73.
 [http://dx.doi.org/10.1007/978-1-4614-6199-9_12] [PMID: 23550010]

[43]
Uenoyama Y, Nakamura S, Hayakawa Y, et al. Lack of pulse and surge modes and glutamatergic stimulation of luteinising hormone release in Kiss1 knockout rats. J Neuroendocrinol  2015; 27(3): 187-97.
 [http://dx.doi.org/10.1111/jne.12257] [PMID: 25582792]

[44]
Han SY, McLennan T, Czieselsky K, Herbison AE. Selective optogenetic activation of arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion. Proc Natl Acad Sci USA  2015; 112(42): 13109-14.
 [http://dx.doi.org/10.1073/pnas.1512243112] [PMID: 26443858]

[45]
Clarkson J, Han SY, Piet R, et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc Natl Acad Sci USA  2017; 114(47): E10216-23.
 [http://dx.doi.org/10.1073/pnas.1713897114] [PMID: 29109258]

[46]
Ohkura S, Takase K, Matsuyama S, et al. Gonadotrophin-releasing hormone pulse generator activity in the hypothalamus of the goat. J Neuroendocrinol  2009; 21(10): 813-21.
 [http://dx.doi.org/10.1111/j.1365-2826.2009.01909.x] [PMID: 19678868]

[47]
Wakabayashi Y, Nakada T, Murata K, et al. Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J Neurosci  2010; 30(8): 3124-32.
 [http://dx.doi.org/10.1523/JNEUROSCI.5848-09.2010] [PMID: 20181609]

[48]
Goodman RL, Hileman SM, Nestor CC, et al. Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. Endocrinology  2013; 154(11): 4259-69.
 [http://dx.doi.org/10.1210/en.2013-1331] [PMID: 23959940]

[49]
Jeong HR, Lee HS, Hwang JS. Makorin ring finger 3 gene analysis in Koreans with familial precocious puberty. J Pediatr Endocrinol Metab  2017; 30(11): 1197-201.
 [http://dx.doi.org/10.1515/jpem-2016-0471] [PMID: 28988223]

[50]
Bhaskaran M, Mohan M. MicroRNAs: History, biogenesis, and their evolving role in animal development and disease. Vet Pathol  2014; 51(4): 759-74.
 [http://dx.doi.org/10.1177/0300985813502820] [PMID: 24045890]

[51]
Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature  2000; 403(6772): 901-6.
 [http://dx.doi.org/10.1038/35002607] [PMID: 10706289]

[52]
Wienholds E, Kloosterman WP, Miska E, et al. MicroRNA expression in zebrafish embryonic development. Science  2005; 309(5732): 310-1.
 [http://dx.doi.org/10.1126/science.1114519] [PMID: 15919954]

[53]
Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science  2004; 303(5654): 83-6.
 [http://dx.doi.org/10.1126/science.1091903] [PMID: 14657504]

[54]
Messina A, Langlet F, Chachlaki K, et al. A microRNA switch regulates the rise in hypothalamic GnRH production before puberty. Nat Neurosci  2016; 19(6): 835-44.
 [http://dx.doi.org/10.1038/nn.4298] [PMID: 27135215]

[55]
Ong KK, Elks CE, Li S, et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat Genet  2009; 41(6): 729-33.
 [http://dx.doi.org/10.1038/ng.382] [PMID: 19448623]

[56]
He C, Kraft P, Chen C, et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet  2009; 41(6): 724-8.
 [http://dx.doi.org/10.1038/ng.385] [PMID: 19448621]

[57]
Zhu H, Shah S, Shyh-Chang N, et al. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat Genet  2010; 42(7): 626-30.
 [http://dx.doi.org/10.1038/ng.593] [PMID: 20512147]

[58]
Sangiao-Alvarellos S, Manfredi-Lozano M, Ruiz-Pino F, et al. Changes in hypothalamic expression of the Lin28/let-7 system and related microRNAs during postnatal maturation and after experimental manipulations of puberty. Endocrinology  2013; 154(2): 942-55.
 [http://dx.doi.org/10.1210/en.2012-2006] [PMID: 23291449]

[59]
Grieco A, Rzeczkowska P, Alm C, Palmert MR. Investigation of peripubertal expression of Lin28a and Lin28b in C57BL/6 female mice. Mol Cell Endocrinol  2013; 365(2): 241-8.
 [http://dx.doi.org/10.1016/j.mce.2012.10.025] [PMID: 23138112]

[60]
Parent AS, Matagne V, Westphal M, Heger S, Ojeda S, Jung H. Gene expression profiling of hypothalamic hamartomas: A search for genes associated with central precocious puberty. Horm Res  2008; 69(2): 114-23.
 [http://dx.doi.org/10.1159/000111815] [PMID: 18059092]

[61]
Shimogori T, Lee DA, Miranda-Angulo A, et al. A genomic atlas of mouse hypothalamic development. Nat Neurosci  2010; 13(6): 767-75.
 [http://dx.doi.org/10.1038/nn.2545] [PMID: 20436479]

[62]
Boles NC, Hirsch SE, Le S, et al. NPTX1 regulates neural lineage specification from human pluripotent stem cells. Cell Rep  2014; 6(4): 724-36.
 [http://dx.doi.org/10.1016/j.celrep.2014.01.026] [PMID: 24529709]

[63]
Liu H, Kong X, Chen F. Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation. Oncotarget  2017; 8(49): 85102-9.
 [http://dx.doi.org/10.18632/oncotarget.19347] [PMID: 29156706]

[64]
Liu M, Fan L, Gong CX. A novel heterozygous MKRN3 nonsense mutation in a Chinese girl with idiopathic central precocious puberty. A case report Medicine  2020; 99(38): e22295.
 [http://dx.doi.org/10.1097/MD.0000000000022295] [PMID: 32957387]

[65]
Varimo T, Iivonen AP, Kansakoski J, et al. Familial central precocious puberty: Two novel MKRN3 mutations. Pediatr Res 2020.
 [http://dx.doi.org/10.1111/cen.12854] [PMID: 33214675]

[66]
Abreu AP, Toro CA, Song YB, et al. MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons. J Clin Invest  2020; 130(8): 4486-500.
 [http://dx.doi.org/10.1172/JCI136564] [PMID: 32407292]

[67]
Fanis P, Skordis N, Toumba M, et al. Central precocious puberty caused by novel mutations in the promoter and 5′-UTR region of the imprinted MKRN3 gene. Front Endocrinol  2019; 10: 677.
 [http://dx.doi.org/10.3389/fendo.2019.00677] [PMID: 31636607]

[68]
Lu W, Wang J, Li C, Sun M, Hu R, Wang W. A novel mutation in 5′-UTR of Makorin ring finger 3 gene associated with the familial precocious puberty. Acta Biochim Biophys Sin  2018; 50(12): 1291-3.
 [http://dx.doi.org/10.1093/abbs/gmy124] [PMID: 30462148]

[69]
Macedo DB, França MM, Montenegro LR, et al. Central precocious puberty caused by a heterozygous deletion in the MKRN3 promoter region. Neuroendocrinology  2018; 107(2): 127-32.
 [http://dx.doi.org/10.1159/000490059] [PMID: 29763903]

[70]
Simon D, Ba I, Mekhail N, et al. Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty. Eur J Endocrinol  2016; 174(1): 1-8.
 [http://dx.doi.org/10.1530/EJE-15-0488] [PMID: 26431553]

[71]
Ortiz-Cabrera NV, Riveiro-Álvarez R, López-Martínez MÁ, et al. Clinical exome sequencing reveals MKRN3 pathogenic variants in familial and nonfamilial idiopathic central precocious puberty. Horm Res Paediatr  2017; 87(2): 88-94.
 [http://dx.doi.org/10.1159/000453262] [PMID: 27931036]

[72]
Lee HS, Jin HS, Shim YS, et al. Low frequency of MKRN3 mutations in central precocious puberty among Korean girls. Horm Metab Res  2016; 48(2): 118-22.
 [http://dx.doi.org/10.1055/s-0035-1548938] [PMID: 25938887]

[73]
Schreiner F, Gohlke B, Hamm M, Korsch E, Woelfle J. MKRN3 mutations in familial central precocious puberty. Horm Res Paediatr  2014; 82(2): 122-6.
 [http://dx.doi.org/10.1159/000362815] [PMID: 25011910]

[74]
Simsek E, Demiral M, Ceylaner S, Kırel B. Two Frameshift Mutations in MKRN3 in Turkish Patients with Familial Central Precocious Puberty. Horm Res Paediatr  2017; 87(6): 405-11.
 [http://dx.doi.org/10.1159/000450923] [PMID: 27798941]

[75]
Grandone A, Capristo C, Cirillo G, et al. Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty. Horm Res Paediatr  2017; 88(3-4): 194-200.
 [http://dx.doi.org/10.1159/000477441] [PMID: 28672280]

[76]
Macedo DB, Abreu AP, Reis AC, 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(6): E1097-103.
 [http://dx.doi.org/10.1210/jc.2013-3126] [PMID: 24628548]

[77]
Dimitrova-Mladenova MS, Stefanova EM, Glushkova M, et al. Males with paternally inherited MKRN3 mutations may be asymptomatic. J Pediatr  2016; 179: 263-5.
 [http://dx.doi.org/10.1016/j.jpeds.2016.08.065] [PMID: 27640350]

[78]
Stecchini MF, Macedo DB, Reis AC, et al. Time course of central precocious puberty development caused by an MKRN3 gene mutation: A prismatic case. Horm Res Paediatr  2016; 86(2): 126-30.
 [http://dx.doi.org/10.1159/000447515] [PMID: 27424312]

[79]
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(3): e93-6.
 [http://dx.doi.org/10.1515/cclm-2015-0408] [PMID: 26402883]

[80]
Aycan Z, Savaş-Erdeve Ş, Çetinkaya S, et al. Investigation of MKRN3 mutation in patients with familial central precocious puberty. J Clin Res Pediatr Endocrinol  2018; 10(3): 223-9.
 [http://dx.doi.org/10.4274/jcrpe.5506] [PMID: 29537379]

[81]
Chen T, Chen L, Wu H, et al. Low Frequency of MKRN3 and DLK1 variants in Chinese children with central precocious puberty. Int J Endocrinol  2019; 2019: 9879367.
 [http://dx.doi.org/10.1155/2019/9879367] [PMID: 31687022]

[82]
Nishioka J, Shima H, Fukami M, et al. The first Japanese case of central precocious puberty with a novel MKRN3 mutation. Hum Genome Var  2017; 4(1): 17017.
 [http://dx.doi.org/10.1038/hgv.2017.17] [PMID: 28546864]

[83]
Christoforidis A, Skordis N, Fanis P, et al. A novel MKRN3 nonsense mutation causing familial central precocious puberty. Endocrine  2017; 56(2): 446-9.
 [http://dx.doi.org/10.1007/s12020-017-1232-6] [PMID: 28132164]

[84]
Neocleous V, Shammas C, Phelan MM, Nicolaou S, Phylactou LA, Skordis N. In silico analysis of a novel MKRN3 missense mutation in familial central precocious puberty. Clin Endocrinol  2016; 84(1): 80-4.
 [http://dx.doi.org/10.1111/cen.12854] [PMID: 26173472]

[85]
Bessa DS, Macedo DB, Brito VN, et al. High frequency of MKRN3 mutations in male central precocious puberty previously classified as idiopathic. Neuroendocrinology  2017; 105(1): 17-25.
 [http://dx.doi.org/10.1159/000446963] [PMID: 27225315]

[86]
Settas N, Dacou-Voutetakis C, Karantza M, Kanaka-Gantenbein C, Chrousos GP, Voutetakis A. Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene. J Clin Endocrinol Metab  2014; 99(4): E647-51.
 [http://dx.doi.org/10.1210/jc.2013-4084] [PMID: 24438377]

[87]
Känsäkoski J, Raivio T, Juul A, Tommiska J. A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty. Pediatr Res  2015; 78(6): 709-11.
 [http://dx.doi.org/10.1038/pr.2015.159] [PMID: 26331766]

[88]
Pagani S, Calcaterra V, Acquafredda G, et al. MKRN3 and KISS1R mutations in precocious and early puberty. Ital J Pediatr  2020; 46(1): 39.
 [http://dx.doi.org/10.1186/s13052-020-0808-6] [PMID: 32228714]

[89]
de Vries L, Gat-Yablonski G, Dror N, Singer A, Phillip M. A novel MKRN3 missense mutation causing familial precocious puberty. Hum Reprod  2014; 29(12): 2838-43.
 [http://dx.doi.org/10.1093/humrep/deu256] [PMID: 25316453]

[90]
Soriano-Guillén L, Argente J. Central precocious puberty, functional and tumor-related. Best Pract Res Clin Endocrinol Metab  2019; 33(3): 101262.
 [http://dx.doi.org/10.1016/j.beem.2019.01.003] [PMID: 30733078]

[91]
Ojeda SR, Lomniczi A. Puberty in 2013: Unravelling the mystery of puberty. Nat Rev Endocrinol  2014; 10(2): 67-9.
 [http://dx.doi.org/10.1038/nrendo.2013.233] [PMID: 24275741]

[92]
Mul D, Hughes IA. The use of GnRH agonists in precocious puberty. Eur J Endocrinol  2008; 159 (Suppl. 1): S3-8.
 [http://dx.doi.org/10.1530/EJE-08-0814] [PMID: 19064674]

[93]
Chen M, Eugster EA. Central precocious puberty: Update on diagnosis and treatment. Paediatr Drugs  2015; 17(4): 273-81.
 [http://dx.doi.org/10.1007/s40272-015-0130-8] [PMID: 25911294]

[94]
Witchel SF, Baens-Bailon RG, Lee PA. Treatment of central precocious puberty: Comparison of urinary gonadotropin excretion and Gonadotropin-Releasing Hormone (GnRH) stimulation tests in monitoring GnRH analog therapy. J Clin Endocrinol Metab  1996; 81(4): 1353-6.
 [http://dx.doi.org/10.4.86363320.1210/jcem.8] [PMID: 8636332]

[95]
Roth C. Therapeutic potential of GnRH antagonists in the treatment of precocious puberty. Expert Opin Investig Drugs  2002; 11(9): 1253-9.
 [http://dx.doi.org/10.1517/13543784.11.9.1253] [PMID: 12225246]

[96]
Hirsch HJ, Gillis D, Strich D, et al. The histrelin implant: A novel treatment for central precocious puberty. Pediatrics  2005; 116(6): e798-802.
 [http://dx.doi.org/10.1542/peds.2005-0538] [PMID: 16322137]

[97]
Silverman LA, Neely EK, Kletter GB, et al. Long-term continuous suppression with once-yearly histrelin subcutaneous implants for the treatment of central precocious puberty: A final report of a phase 3 multicenter trial. J Clin Endocrinol Metab  2015; 100(6): 2354-63.
 [http://dx.doi.org/10.1210/jc.2014-3031] [PMID: 25803268]

[98]
Abbara A, Dhillo WS. Makorin rings the kisspeptin bell to signal pubertal initiation. J Clin Invest  2020; 130(8): 3957-60.
 [http://dx.doi.org/10.1172/JCI139586] [PMID: 32687068]

[99]
Martínez-Aguayo A, Hernández MI, Beas F, et al. Treatment of central precocious puberty with triptorelin 11.25 mg depot formulation. J Pediatr Endocrinol Metab  2006; 19(8): 963-70.
 [http://dx.doi.org/10.1515/JPEM.2006.19.8.963] [PMID: 16995580]
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DOI https://dx.doi.org/10.2174/1566524022666220624105430	Print ISSN 1566-5240
Publisher Name Bentham Science Publisher	Online ISSN 1875-5666
当代分子医药

马科林无名指蛋白3（MKRN3）在青春期启动和中枢性早熟（CPP）发展过程中的关键作用

摘要

当代分子医药

马科林无名指蛋白3（MKRN3）在青春期启动和中枢性早熟（CPP）发展过程中的关键作用

摘要

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