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Semin Reprod Med 2019; 37(04): 166-173
DOI: 10.1055/s-0039-3400965
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions

Lydie Naulé
1   Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
,
Ursula B. Kaiser
1   Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
› Author Affiliations
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Publication History

Publication Date:
23 January 2020 (online)

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Abstract

Puberty is a critical period of development regulated by genetic, nutritional, and environmental factors. The role of makorin ring finger protein 3 (MKRN3) in the regulation of pubertal timing was revealed when loss-of-function mutations were identified in patients with central precocious puberty (CPP). To date, MKRN3 mutations are the most common known genetic cause of CPP. MKRN3 is a member of the makorin family of ubiquitin ligases, together with MKRN1 and MKRN2. The Mkrn genes have been identified in both vertebrates and invertebrates and show high evolutionary conservation of their gene and protein structures. While the existence of Mkrn orthologues in a wide spectrum of species suggests a vital cellular role of the makorins, their role in puberty initiation and endocrine functions is just beginning to be investigated. In this review, we discuss recent studies that have shown the involvement of Mkrn3 and other makorins in the regulation of pubertal development and other endocrine functions, including metabolism and fertility, as well as their underlying mechanisms of action.

Keywords

MKRN3 - puberty - E3 ubiquitin ligase - makorins
 

  • References

  • 1 Abreu AP, Kaiser UB. Pubertal development and regulation. Lancet Diabetes Endocrinol 2016; 4 (03) 254-264
    CrossrefPubMedGoogle Scholar
  • 2 Plant TM. Neuroendocrine control of the onset of puberty. Front Neuroendocrinol 2015; 38: 73-88
    CrossrefPubMedGoogle Scholar
  • 3 Avendaño MS, Vazquez MJ, Tena-Sempere M. Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty. Hum Reprod Update 2017; 23 (06) 737-763
    CrossrefPubMedGoogle Scholar
  • 4 Palmert MR, Boepple PA. Variation in the timing of puberty: clinical spectrum and genetic investigation. J Clin Endocrinol Metab 2001; 86 (06) 2364-2368
    CrossrefPubMedGoogle Scholar
  • 5 Schwanzel-Fukuda M, Bick D, Pfaff DW. Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Brain Res Mol Brain Res 1989; 6 (04) 311-326
    CrossrefPubMedGoogle Scholar
  • 6 Bianco SDC, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol 2009; 5 (10) 569-576
    CrossrefPubMedGoogle Scholar
  • 7 Clarke SA, Dhillo WS. Kisspeptin across the human lifespan: evidence from animal studies and beyond. J Endocrinol 2016; 229 (03) R83-R98
    CrossrefPubMedGoogle Scholar
  • 8 Seminara SB, Messager S, Chatzidaki EE. , et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349 (17) 1614-1627
    CrossrefPubMedGoogle Scholar
  • 9 de Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100 (19) 10972-10976
    CrossrefPubMedGoogle Scholar
  • 10 Teles MG, Bianco SDC, Brito VN. , et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 2008; 358 (07) 709-715
    CrossrefPubMedGoogle Scholar
  • 11 Silveira LG, Noel SD, Silveira-Neto AP. , et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab 2010; 95 (05) 2276-2280
    CrossrefPubMedGoogle Scholar
  • 12 Topaloglu AK, Reimann F, Guclu M. , et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009; 41 (03) 354-358
    CrossrefPubMedGoogle Scholar
  • 13 Young J, Bouligand J, Francou B. , et al. TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J Clin Endocrinol Metab 2010; 95 (05) 2287-2295
    CrossrefPubMedGoogle Scholar
  • 14 Gianetti E, Tusset C, Noel SD. , et al. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab 2010; 95 (06) 2857-2867
    CrossrefPubMedGoogle Scholar
  • 15 Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci 2009; 29 (38) 11859-11866
    CrossrefPubMedGoogle Scholar
  • 16 Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 2010; 151 (08) 3479-3489
    CrossrefPubMedGoogle Scholar
  • 17 Clarkson J, Herbison AE. Development of GABA and glutamate signaling at the GnRH neuron in relation to puberty. Mol Cell Endocrinol 2006; 254-255: 32-38
    CrossrefPubMedGoogle Scholar
  • 18 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) 2467-2475
    CrossrefPubMedGoogle Scholar
  • 19 Dauber A, Cunha-Silva M, Macedo DB. , et al. Paternally inherited DLK1 deletion associated with familial central precocious puberty. J Clin Endocrinol Metab 2017; 102 (05) 1557-1567
    CrossrefPubMedGoogle Scholar
  • 20 Gomes LG, Cunha-Silva M, Crespo RP. , et al. DLK1 is a novel link between reproduction and metabolism. J Clin Endocrinol Metab 2019; 104 (06) 2112-2120
    CrossrefPubMedGoogle Scholar
  • 21 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 (04) E647-E651
    CrossrefPubMedGoogle Scholar
  • 22 Schreiner F, Gohlke B, Hamm M, Korsch E, Woelfle J. MKRN3 mutations in familial central precocious puberty. Horm Res Paediatr 2014; 82 (02) 122-126
    CrossrefPubMedGoogle Scholar
  • 23 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) 2838-2843
    CrossrefPubMedGoogle Scholar
  • 24 Macedo DB, Abreu AP, Reis ACS. , 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 (06) E1097-E1103
    CrossrefPubMedGoogle Scholar
  • 25 Grandone A, Cantelmi G, Cirillo G. , et al. A case of familial central precocious puberty caused by a novel mutation in the makorin RING finger protein 3 gene. BMC Endocr Disord 2015; 15: 60
    CrossrefPubMedGoogle Scholar
  • 26 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 (01) 1-8
    CrossrefPubMedGoogle Scholar
  • 27 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 (06) 405-411
    CrossrefPubMedGoogle Scholar
  • 28 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 (02) 118-122
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 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 (02) 88-94
    CrossrefPubMedGoogle Scholar
  • 30 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: 17017
    CrossrefPubMedGoogle Scholar
  • 31 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 (01) 17-25
    CrossrefPubMedGoogle Scholar
  • 32 Stecchini MF, Macedo DB, Reis ACS. , et al. Time course of central precocious puberty development caused by an MKRN3 gene mutation: a prismatic case. Horm Res Paediatr 2016; 86 (02) 126-130
    CrossrefPubMedGoogle Scholar
  • 33 Valadares LP, Meireles CG, De Toledo IP. , et al. MKRN3 mutations in central precocious puberty: a systematic review and meta-analysis. J Endocr Soc 2019; 3 (05) 979-995
    CrossrefPubMedGoogle Scholar
  • 34 Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index. Pediatrics 2009; 123 (01) 84-88
    CrossrefPubMedGoogle Scholar
  • 35 Day FR, Elks CE, Murray A, Ong KK, Perry JRB. Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study. Sci Rep 2015; 5: 11208
    CrossrefPubMedGoogle Scholar
  • 36 Day FR, Thompson DJ, Helgason H. , et al; LifeLines Cohort Study; InterAct Consortium; kConFab/AOCS Investigators; Endometrial Cancer Association Consortium; Ovarian Cancer Association Consortium; PRACTICAL consortium. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet 2017; 49 (06) 834-841
    CrossrefPubMedGoogle Scholar
  • 37 Lakshman R, Forouhi NG, Sharp SJ. , et al. Early age at menarche associated with cardiovascular disease and mortality. J Clin Endocrinol Metab 2009; 94 (12) 4953-4960
    CrossrefPubMedGoogle Scholar
  • 38 Perry JRB, Day F, Elks CE. , et al; Australian Ovarian Cancer Study; GENICA Network; kConFab; LifeLines Cohort Study; InterAct Consortium; Early Growth Genetics (EGG) Consortium. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 2014; 514 (7520): 92-97
    PubMedGoogle Scholar
  • 39 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 (05) 783-793
    CrossrefPubMedGoogle Scholar
  • 40 Jong MT, Carey AH, Caldwell KA. , et al. Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader-Willi syndrome genetic region. Hum Mol Genet 1999; 8 (05) 795-803
    CrossrefPubMedGoogle Scholar
  • 41 Hall TMT. Multiple modes of RNA recognition by zinc finger proteins. Curr Opin Struct Biol 2005; 15 (03) 367-373
    CrossrefPubMedGoogle Scholar
  • 42 Deshaies RJ, Joazeiro CAP. RING domain E3 ubiquitin ligases. Annu Rev Biochem 2009; 78: 399-434
    CrossrefPubMedGoogle Scholar
  • 43 Gray TA, Hernandez L, Carey AH. , et al. The ancient source of a distinct gene family encoding proteins featuring RING and C(3)H zinc-finger motifs with abundant expression in developing brain and nervous system. Genomics 2000; 66 (01) 76-86
    CrossrefPubMedGoogle Scholar
  • 44 Zhang QH, Ye M, Wu XY. , et al. Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells. Genome Res 2000; 10 (10) 1546-1560
    CrossrefPubMedGoogle Scholar
  • 45 Gray TA, Azama K, Whitmore K, Min A, Abe S, Nicholls RD. Phylogenetic conservation of the makorin-2 gene, encoding a multiple zinc-finger protein, antisense to the RAF1 proto-oncogene. Genomics 2001; 77 (03) 119-126
    CrossrefPubMedGoogle Scholar
  • 46 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: 721
    CrossrefPubMedGoogle Scholar
  • 47 Rapkins RW, Hore T, Smithwick M. , et al. Recent assembly of an imprinted domain from non-imprinted components. PLoS Genet 2006; 2 (10) e182
    CrossrefPubMedGoogle Scholar
  • 48 Gray TA, Wilson A, Fortin PJ, Nicholls RD. The putatively functional Mkrn1-p1 pseudogene is neither expressed nor imprinted, nor does it regulate its source gene in trans. Proc Natl Acad Sci U S A 2006; 103 (32) 12039-12044
    CrossrefPubMedGoogle Scholar
  • 49 Kim JH, Park SM, Kang MR. , et al. Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT. Genes Dev 2005; 19 (07) 776-781
    CrossrefPubMedGoogle Scholar
  • 50 Lee E-W, Lee MS, Camus S. , et al. Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis. EMBO J 2009; 28 (14) 2100-2113
    CrossrefPubMedGoogle Scholar
  • 51 Kim JH, Park KW, Lee EW. , et al. Suppression of PPARγ through MKRN1-mediated ubiquitination and degradation prevents adipocyte differentiation. Cell Death Differ 2014; 21 (04) 594-603
    CrossrefPubMedGoogle Scholar
  • 52 Lee MS, Han HJ, Han SY. , et al. Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation. Nat Commun 2018; 9 (01) 3404
    CrossrefPubMedGoogle Scholar
  • 53 Omwancha J, Zhou XF, Chen SY. , et al. Makorin RING finger protein 1 (MKRN1) has negative and positive effects on RNA polymerase II-dependent transcription. Endocrine 2006; 29 (02) 363-373
    CrossrefPubMedGoogle Scholar
  • 54 Miroci H, Schob C, Kindler S. , et al. Makorin ring zinc finger protein 1 (MKRN1), a novel poly(A)-binding protein-interacting protein, stimulates translation in nerve cells. J Biol Chem 2012; 287 (02) 1322-1334
    CrossrefPubMedGoogle Scholar
  • 55 Cassar PA, Carpenedo RL, Samavarchi-Tehrani P. , et al. Integrative genomics positions MKRN1 as a novel ribonucleoprotein within the embryonic stem cell gene regulatory network. EMBO Rep 2015; 16 (10) 1334-1357
    PubMedGoogle Scholar
  • 56 Qian X, Wang L, Zheng B. , et al. Deficiency of Mkrn2 causes abnormal spermiogenesis and spermiation, and impairs male fertility. Sci Rep 2016; 6: 39318
    CrossrefPubMedGoogle Scholar
  • 57 Yang PH, Cheung WKC, Peng Y. , et al. Makorin-2 is a neurogenesis inhibitor downstream of phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signal. J Biol Chem 2008; 283 (13) 8486-8495
    CrossrefPubMedGoogle Scholar
  • 58 Cheung WKC, Yang PH, Huang QH. , et al. Identification of protein domains required for makorin-2-mediated neurogenesis inhibition in Xenopus embryos. Biochem Biophys Res Commun 2010; 394 (01) 18-23
    CrossrefPubMedGoogle Scholar
  • 59 Shin C, Ito Y, Ichikawa S, Tokunaga M, Sakata-Sogawa K, Tanaka T. MKRN2 is a novel ubiquitin E3 ligase for the p65 subunit of NF-κB and negatively regulates inflammatory responses. Sci Rep 2017; 7: 46097
    CrossrefPubMedGoogle Scholar
  • 60 Kanber D, Giltay J, Wieczorek D. , et al. A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome. Eur J Hum Genet 2009; 17 (05) 582-590
    CrossrefPubMedGoogle Scholar
  • 61 Driscoll DJ, Waters MF, Williams CA. , et al. A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes. Genomics 1992; 13 (04) 917-924
    CrossrefPubMedGoogle Scholar
  • 62 Hershko A, Razin A, Shemer R. Imprinted methylation and its effect on expression of the mouse Zfp127 gene. Gene 1999; 234 (02) 323-327
    CrossrefPubMedGoogle Scholar
  • 63 Nicholls RD, Saitoh S, Horsthemke B. Imprinting in Prader-Willi and Angelman syndromes. Trends Genet 1998; 14 (05) 194-200
    CrossrefPubMedGoogle Scholar
  • 64 Liu H, Kong X, Chen F. Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation. Oncotarget 2017; 8 (49) 85102-85109
    CrossrefPubMedGoogle Scholar
  • 65 Lund C, Pulli K, Yellapragada V. , et al. Development of gonadotropin-releasing hormone-secreting neurons from human pluripotent stem cells. Stem Cell Reports 2016; 7 (02) 149-157
    CrossrefPubMedGoogle Scholar
  • 66 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 (Lausanne) 2019; 10: 48
    CrossrefPubMedGoogle Scholar
  • 67 Tran HT, Cho E, Jeong S. , et al. Makorin 1 regulates developmental timing in drosophila. Mol Cells 2018; 41 (12) 1024-1032
    PubMedGoogle Scholar
  • 68 Jeong EB, Jeong SS, Cho E, Kim EY. Makorin 1 is required for Drosophila oogenesis by regulating insulin/Tor signaling. PLoS One 2019; 14 (04) e0215688
    CrossrefPubMedGoogle Scholar
  • 69 Herrera RA, Kiontke K, Fitch DHA. Makorin ortholog LEP-2 regulates LIN-28 stability to promote the juvenile-to-adult transition in Caenorhabditis elegans . Development 2016; 143 (05) 799-809
    CrossrefPubMedGoogle Scholar
  • 70 Lawson H, Vuong E, Miller RM, Kiontke K, Fitch DH, Portman DS. The Makorin lep-2 and the lncRNA lep-5 regulate lin-28 to schedule sexual maturation of the C. elegans nervous system. eLife 2019; 8: e43660
    CrossrefPubMedGoogle Scholar