Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls

Hagen, Casper P.; Sørensen, Kaspar; Mieritz, Mikkel G.; Johannsen, Trine Holm; Almstrup, Kristian; Juul, Anders

doi:10.1210/jc.2014-4462

Cited by 86Hypothalamic control of reproductive hormonesSexual Differentiation and DisordersGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls

Hagen, Casper P., Sørensen, Kaspar, Mieritz, Mikkel G., Johannsen, Trine Holm, Almstrup, Kristian, Juul, Anders·2015·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2014-4462

Open this paper in CoChat — free account

Abstract

CONTEXT: Puberty is initiated by a complex interaction of suppressing and stimulating factors. Genetic studies of familial central precocious puberty have suggested makorin ring finger protein 3 (MKRN3) as a major inhibitor of GnRH secretion during childhood. Furthermore, genetic variation near MKRN3 (rs12148769) affects age at menarche in healthy girls. OBJECTIVE: The purpose of this study was to evaluate whether serum levels of MKRN3 declined before pubertal onset in healthy girls. DESIGN: This was a population-based longitudinal study of healthy Danish girls and a cohort study of early maturing girls. SETTING: The study was performed in the general community and in a tertiary referral center for pediatric endocrinology. PATIENTS OR OTHER PARTICIPANTS: Healthy girls (n = 38) aged 9.3 years (range, 5.9-11.3 years) at baseline and followed for 6.0 years (2.7-7.6 years) (2006-2014) with blood sampling every 6 months and early maturing girls (n = 13) with breast development ay <8.3 years of age were included. MAIN OUTCOME MEASURES: Serum levels of MKRN3 were measured in 354 samples (median, 9 per girl; range, 2-14 per girl), and genotyping of variants near MKRN3 (rs12148769 and rs12439354) was performed. RESULTS: MKRN3 concentrations declined preceding pubertal onset; the geometric mean (95% confidence interval) 3 years before pubertal onset vs the last visit before pubertal onset was 304 pg/mL (264-350 pg/mL) vs 257 pg/mL (243-273 pg/mL), corresponding to a reduction of 15% (1-27%) (P = .033). In prepubertal girls, circulating MKRN3 correlated negatively with gonadotropin levels: for FSH, r = -0.262 (P = .015) and for LH, r = -0.226 (P = .037). After adjustment, MKRN3 levels were lower in early maturing girls than in age-matched prepubertal girls: 171 pg/mL (<25-333 pg/mL) vs 262 pg/mL (94-624 pg/mL) (P = .051). Genetic variants near MKRN3 did not correlate with serum levels of MKRN3. CONCLUSIONS: Declining levels of circulating MKRN3 preceded pubertal onset. The negative correlation between MKRN3 and gonadotropins further supports MKRN3 as a major regulator of hypothalamic GnRH secretion during childhood. Undetectable or low MKRN3 levels were observed in a subgroup of patients with early onset of puberty.

Integrity signals

Registry

Crossref · 10.1210/jc.2014-4462

Cites

28 of 28 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

MKRN3 is the most common genetic defect associated with central precocious puberty so far; families with central precocious puberty from several different ethnic groups harbour mutations in this gene.
“MKRN3 is the most common genetic defect associated with central precocious puberty so far; families with central precocious puberty from several different ethnic groups harbour mutations in this gene.52,71–76”
From Pubertal development and regulation (2016) · cites this paper as [72]

Growth at Adolescence
Tanner, J. M. (1978) · Medical Entomology and Zoology · Cited by 3,742 · see citing works
The GPR54 Gene as a Regulator of Puberty
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S., Shagoury, J. K., Bo-Abbas, Y., Kuohung, W., Schwinof, K. M., Hendrick, A. G., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa035322 · Cited by 2,557 · see citing works
Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., & Milgrom, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834399100 · Cited by 2,431 · see citing works
TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction
Topaloglu, A. K., Reimann, F., Guclu, M., Yalin, A. S., Kotan, L. D., Porter, K. M., Serin, A., Mungan, N. O., Cook, J. R., Ozbek, M. N., et al. (2009) · Nature Genetics · doi:10.1038/ng.306 · Cited by 961 · see citing works
Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children
Carel, J., Eugster, E. A., Rogol, A. D., Ghizzoni, L., Palmert, M. R., & on behalf of the members of the ESPE-LWPES GnRH Analogs Consensus Conference Group (2009) · PEDIATRICS · doi:10.1542/peds.2008-1783 · Cited by 816 · see citing works
Recent decline in age at breast development: The Copenhagen Puberty Study
Aksglaede, L., Sørensen, K., Petersen, J. H., Skakkebæk, N. E., & Juul, A. (2009) · Pediatrics · doi:10.1542/peds.2008-2491 · Cited by 626 · see citing works
Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
Study, A. O. C., Perry, J. R. B., The GENICA Network, kConFab, Study, T. L. C., The InterAct Consortium, Early Growth Genetics (EGG) Consortium, Day, F., Elks, C. E., Sulem, P., et al. (2014) · Nature · doi:10.1038/nature13545 · Cited by 604 · see citing works
Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3
Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1302160 · Cited by 534 · see citing works
Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
The GIANT Consortium, Elks, C. E., Perry, J. R. B., Sulem, P., Chasman, D. I., Franceschini, N., He, C., Lunetta, K. L., Visser, J. A., Byrne, E. M., et al. (2010) · Nature Genetics · doi:10.1038/ng.714 · Cited by 504 · see citing works
InactivatingKISS1Mutation and Hypogonadotropic Hypogonadism
Topaloglu, A. K., Tello, J. A., Kotan, L. D., Ozbek, M. N., Yilmaz, M. B., Erdogan, S., Gurbuz, F., Temiz, F., Millar, R. P., & Yuksel, B. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1111184 · Cited by 467 · see citing works
Recent changes in pubertal timing in healthy danish boys: associations with body mass index
Sørensen, K., Aksglaede, L., Petersen, J. H., & Juul, A. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1478 · Cited by 393 · see citing works
Epigenetic control of female puberty
Lomniczi, A., Loche, A., Castellano, J. M., Rønnekleiv, O. K., Bosch, M. A., Kaidar, G., Knoll, J. G., Wright, H., Pfeifer, G. P., & Ojeda, S. R. (2013) · Nature Neuroscience · doi:10.1038/nn.3319 · Cited by 307 · see citing works
A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader–Willi syndrome critical region
Jong, M. T. C., Gray, T. A., Ji, Y., Glenn, C. C., Saitoh, S., Driscoll, D. J., & Nicholls, R. D. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.5.783 · Cited by 230 · see citing works
Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3
Macedo, D. B., Abreu, A. P., Reis, A. C. S., Montenegro, L. R., Dauber, A., Beneduzzi, D., Cukier, P., Silveira, L. F. G., Teles, M. G., Carroll, R. S., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3126 · Cited by 140 · see citing works
Individual serum levels of anti-Mullerian hormone in healthy girls persist through childhood and adolescence: a longitudinal cohort study
Hagen, C. P., Aksglæde, L., Sørensen, K., Mouritsen, A., Andersson, A., Petersen, J. H., Main, K. M., & Juul, A. (2012) · Human Reproduction · doi:10.1093/humrep/der435 · Cited by 131 · see citing works
Pubertal maturation of the internal genitalia: an ultrasound evaluation of 166 healthy girls
Holm, K., Laursen, E. M., Brocks, V., & Müller, J. (1995) · Ultrasound in Obstetrics and Gynecology · doi:10.1046/j.1469-0705.1995.06030175.x · Cited by 130 · see citing works
Ultrasound evaluation of uterine and ovarian size from birth to puberty
Haber, H. P., & Mayer, E. I. (1994) · Pediatric Radiology · doi:10.1007/bf02017650 · Cited by 120 · see citing works
FSH, LH, inhibin B and estradiol levels in Turner syndrome depend on age and karyotype: longitudinal study of 70 Turner girls with or without spontaneous puberty
Hagen, C. P., Main, K. M., Kjaergaard, S., & Juul, A. (2010) · Human Reproduction · doi:10.1093/humrep/deq291 · Cited by 114 · see citing works
Hormone Changes in Peripubertal Girls
Biro, F. M., Pinney, S. M., Huang, B., Baker, E. R., Chandler, D. W., & Dorn, L. D. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-4528 · Cited by 109 · see citing works
Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene
Settas, N., Dacou-Voutetakis, C., Karantza, M., Kanaka-Gantenbein, C., Chrousos, G. P., & Voutetakis, A. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-4084 · Cited by 80 · see citing works
A novel MKRN3 missense mutation causing familial precocious puberty
de Vries, L., Gat‐Yablonski, G., Dror, N., Singer, A., & Phillip, M. (2014) · Human Reproduction · doi:10.1093/humrep/deu256 · Cited by 72 · see citing works
Unravelling the mystery of puberty
Ojeda, S. R., & Lomniczi, A. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.233 · Cited by 72 · see citing works
Circulating AMH Reflects Ovarian Morphology by Magnetic Resonance Imaging and 3D Ultrasound in 121 Healthy Girls
Hagen, C. P., Mouritsen, A., Mieritz, M. G., Tinggaard, J., Wohlfahrt‐Veje, C., Fallentin, E., Brocks, V., Sundberg, K., Jensen, L. N., Anderson, R. A., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3336 · Cited by 66 · see citing works
Insulin Sensitivity and Lipid Profiles in Girls with Central Precocious Puberty before and during Gonadal Suppression
Sørensen, K., Mouritsen, A., Mogensen, S. S., Aksglæde, L., & Juul, A. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0731 · Cited by 64 · see citing works
MKRN3 Mutations in Familial Central Precocious Puberty
Schreiner, F., Gohlke, B., Hamm, M., Korsch, E., & Woelfle, J. (2014) · Hormone Research in Paediatrics · doi:10.1159/000362815 · Cited by 63 · see citing works
The vertebrate makorin ubiquitin ligase gene family has been shaped by large-scale duplication and retroposition from an ancestral gonad-specific, maternal-effect gene
Böhne, A., Darras, A., D'Cotta, H., Baroiller, J., Galiana-Arnoux, D., & Volff, J. (2010) · BMC Genomics · doi:10.1186/1471-2164-11-721 · Cited by 52 · see citing works
Pubertal Onset in Girls is Strongly Influenced by Genetic Variation Affecting FSH Action
Hagen, C. P., Sørensen, K., Aksglæde, L., Mouritsen, A., Mieritz, M. G., Tinggaard, J., Wohlfahrt‐Veje, C., Petersen, J. H., Main, K. M., Meyts, E. R., et al. (2014) · Scientific Reports · doi:10.1038/srep06412 · Cited by 37 · see citing works
pfSNP: An integrated potentially functional SNP resource that facilitates hypotheses generation through knowledge syntheses
Wang, J., Ronaghi, M., Chong, S. S., & Lee, C. G. L. (2010) · Human Mutation · doi:10.1002/humu.21331 · Cited by 33 · see citing works

Flagged first, then by citations

Sorted by citations

Pubertal development and regulation
Abreu, A. P., & Kaiser, U. B. (2016) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00418-0 · Cited by 611 · see citing works
Causes, diagnosis, and treatment of central precocious puberty
Latronico, A. C., Brito, V. N., & Carel, J. (2016) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00380-0 · Cited by 527 · see citing works
Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty
Avendaño, M. S., Vazquez, M. J., & Tena‐Sempere, M. (2017) · Human Reproduction Update · doi:10.1093/humupd/dmx025 · Cited by 139 · see citing works
Delayed Puberty—Phenotypic Diversity, Molecular Genetic Mechanisms, and Recent Discoveries
Howard, S. R., & Dunkel, L. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00248 · Cited by 114 · see citing works
Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty
Simon, D., Ba, I., Mekhail, N., Écosse, E., Paulsen, A., Zénaty, D., Houang, M., Jésuran-Pérelroizen, M., FILIPPO, G. D., Salerno, M., et al. (2015) · European Journal of Endocrinology · doi:10.1530/eje-15-0488 · Cited by 113 · see citing works
GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes
Roberts, S. A., & Kaiser, U. B. (2020) · European Journal of Endocrinology · doi:10.1530/eje-20-0103 · Cited by 114 · see citing works
MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis
Valadares, L. P., Meireles, C. G., de Toledo, I. P., Oliveira, R., Castro, L. C., Abreu, A. P., Carroll, R. S., Latronico, A. C., Kaiser, U. B., Guerra, E. N. S., et al. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2019-00041 · Cited by 106 · see citing works
The Congenital and Acquired Mechanisms Implicated in the Etiology of Central Precocious Puberty
Brito, V. N., Canton, A. P. M., Seraphim, C. E., Abreu, A. P., Macedo, D. B., Mendonca, B. B., Kaiser, U. B., Argente, J., & Latronico, A. C. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnac020 · Cited by 115 · see citing works
Minipuberty of human infancy – A window of opportunity to evaluate hypogonadism and differences of sex development?
Renault, C. H., Aksglæde, L., Wøjdemann, D., Hansen, A., Jensen, R. B., & Juul, A. (2020) · Annals of Pediatric Endocrinology & Metabolism · doi:10.6065/apem.2040094.047 · Cited by 95 · see citing works
High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic
Bessa, D. D. S., Macedo, D. B., Brito, V. N., França, M. M., Montenegro, L. R., Cunha-Silva, M., Silveira, L. F. G., Hummel, T., Bergadá, I., Braslavsky, D. G., et al. (2016) · Neuroendocrinology · doi:10.1159/000446963 · Cited by 80 · see citing works
Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3
Heras, V., Sangiao‐Alvarellos, S., Manfredi-Lozano, M., Sanchez-Tapia, M. J., Ruíz-Pino, F., Roa, J., Lara‐Chica, M., Morrugares, R., Jouy, N., Abreu, A. P., et al. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000532 · Cited by 76 · see citing works
Control of the onset of puberty
Livadas, S., & Chrousos, G. P. (2016) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000386 · Cited by 68 · see citing works
Circulating MKRN3 Levels Decline During Puberty in Healthy Boys
Busch, A. S., Hagen, C. P., Almstrup, K., & Juul, A. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-1488 · Cited by 65 · see citing works
The Genetic Basis of Delayed Puberty
Howard, S. R., & Dunkel, L. (2017) · Neuroendocrinology · doi:10.1159/000481569 · Cited by 62 · see citing works
Constitutional delay of puberty versus congenital hypogonadotropic hypogonadism: Genetics, management and updates
Raivio, T., & Miettinen, P. J. (2019) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2019.101316 · Cited by 63 · see citing works
The Genetic Basis of Delayed Puberty
Howard, S. R. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00423 · Cited by 59 · see citing works
The genetics of pubertal timing in the general population
Cousminer, D. L., Widén, E., & Palmert, M. R. (2015) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000213 · Cited by 48 · see citing works
Genetic, epigenetic and enviromental influencing factors on the regulation of precocious and delayed puberty
Faienza, M. F., Urbano, F., Moscogiuri, L. A., Chiarito, M., Santis, S. D., & Giordano, P. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1019468 · Cited by 50 · see citing works
Syndromic Disorders Caused by Disturbed Human Imprinting
Carli, D., Riberi, E., Ferrero, G. B., & Mussa, A. (2019) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2019.2018.0249 · Cited by 44 · see citing works
MKRN3 Interacts With Several Proteins Implicated in Puberty Timing but Does Not Influence GNRH1 Expression
Yellapragada, V., Liu, X., Lund, C., Känsäkoski, J., Pulli, K., Vuoristo, S., Lundin, K., Tuuri, T., Varjosalo, M. T., & Raivio, T. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00048 · Cited by 42 · see citing works
Pioneering studies on monogenic central precocious puberty
Canton, A. P. M., Seraphim, C. E., Brito, V. N., & Latronico, A. C. (2019) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000164 · Cited by 42 · see citing works
An update on the genetic causes of central precocious puberty
Shin, Y. (2016) · Annals of Pediatric Endocrinology & Metabolism · doi:10.6065/apem.2016.21.2.66 · Cited by 39 · see citing works
Genetics of pubertal timing
Mancini, A., Magnotto, J. C., & Abreu, A. P. (2022) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2022.101618 · Cited by 39 · see citing works
Puberty
Witchel, S. F., & Topaloglu, A. K. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-47912-7.00017-2 · Cited by 40 · see citing works
Neuroendokrine Regulation der Pubertät und ihre Störungen
Heger, S. (2016) · Gynäkologische Endokrinologie · doi:10.1007/s10304-016-0091-1 · Cited by 33 · see citing works
MKRN3 and KISS1R mutations in precocious and early puberty
Pagani, S., Calcaterra, V., Acquafredda, G., Montalbano, C., Bozzola, E., Ferrara, P., Gasparri, M., Villani, A., & Bozzola, M. (2020) · The Italian Journal of Pediatrics/Italian journal of pediatrics · doi:10.1186/s13052-020-0808-6 · Cited by 32 · see citing works
MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study
Grandone, A., Cirillo, G., Sasso, M., Capristo, C., Tornese, G., Marzuillo, P., Luongo, C., Umano, G. R., Festa, A., Coppola, R., et al. (2017) · Endocrine · doi:10.1007/s12020-017-1281-x · Cited by 30 · see citing works
Makorin RING finger protein 3 and central precocious puberty
Maione, L., Naulé, L., & Kaiser, U. B. (2020) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2020.08.003 · Cited by 28 · see citing works
A novel MKRN3 nonsense mutation causing familial central precocious puberty
Christoforidis, A., Skordis, N., Fanis, P., Dimitriadou, M., Sevastidou, M., Phelan, M. M., Neocleous, V., & Phylactou, L. A. (2017) · Endocrine · doi:10.1007/s12020-017-1232-6 · Cited by 28 · see citing works
Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma
Bell, J. L., Hagemann, S., Holien, J. K., Liu, T., Nagy, Z. S., Schulte, J. H., Misiak, D., & Hüttelmaier, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21145098 · Cited by 27 · see citing works
The role of kisspeptin and MKRN3 in the diagnosis of central precocious puberty in girls
Li, M., Chen, Y., Liao, B., Tang, J., Zhong, J., & Lan, D. (2021) · Endocrine Connections · doi:10.1530/ec-21-0182 · Cited by 27 · see citing works
Investigation of MKRN3 Mutation in Patients with Familial Central Precocious Puberty
Aycan, Z., Erdeve, Ş. S., Çetinkaya, S. Ç., Kurnaz, E., Keskın, M., Şahin, N. M., Bayramoğlu, E., & Ceylaner, G. (2018) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.5506 · Cited by 27 · see citing works
Two Frameshift Mutations in MKRN3 in Turkish Patients with Familial Central Precocious Puberty
Şimşek, E., Demiral, M., Ceylaner, S., & Kırel, B. (2016) · Hormone Research in Paediatrics · doi:10.1159/000450923 · Cited by 25 · see citing works
Neurobiology of puberty and its disorders
Witchel, S. F., & Plant, T. M. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-820683-6.00033-6 · Cited by 23 · see citing works
A novel mutation in 5’-UTR of Makorin ring finger 3 gene associated with the familial precocious puberty
Lü, W., Wang, J., Li, C., Sun, M., Hu, R., & Wang, W. (2018) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmy124 · Cited by 23 · see citing works
The Use of Morning Urinary Gonadotropins and Sex Hormones in the Management of Early Puberty in Chinese Girls
Zhan, S., Huang, K., Wu, W., Zhang, D., Liu, A., Dorazio, R. M., Shi, J., Ullah, R., Zhang, L., Wang, J., et al. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab448 · Cited by 21 · see citing works
Delayed and Precocious Puberty: Genetic Underpinnings and Treatments
Gohil, A., & Eugster, E. A. (2020) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2020.08.002 · Cited by 21 · see citing works
Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome
Meader, B. N., Albano, A., Sekizkardes, H., & Delaney, A. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa331 · Cited by 21 · see citing works
Aberrant Notch Signaling Pathway as a Potential Mechanism of Central Precocious Puberty
Shim, Y. S., Lee, H. S., & Hwang, J. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063332 · Cited by 18 · see citing works
Makorin ring finger 3 gene analysis in Koreans with familial precocious puberty
Jeong, H. R., Lee, H. S., & Hwang, J. S. (2017) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2016-0471 · Cited by 15 · see citing works
Circulating levels and the bioactivity of miR-30b increase during pubertal progression in boys
Mørup, N., Stakaitis, R., Main, A. M., Golubickaitė, I., Hagen, C. P., Juul, A., & Almstrup, K. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1120115 · Cited by 14 · see citing works
Circulating makorin ring finger protein 3 levels decline in boys before the clinical onset of puberty
Varimo, T. J., Dunkel, L., Vaaralahti, K., Miettinen, P. J., Hero, M. T., & Raivio, T. (2016) · European Journal of Endocrinology · doi:10.1530/eje-15-1193 · Cited by 13 · see citing works
Serum Makorin ring finger protein 3 values for predicting Central precocious puberty in girls
Jeong, H. R., Lee, H. J., Shim, Y. S., Kang, M. J., Yang, S., & Hwang, I. T. (2019) · Gynecological Endocrinology · doi:10.1080/09513590.2019.1576615 · Cited by 12 · see citing works
Evaluation of Serum Makorin Ring Finger Protein 3 (MKRN3) Levels in Girls With Idiopathic Central Precocious Puberty and Premature Thelarche
Ge, W., wang, H., SHAO, H.-J., LIU, H.-W., & Xu, R. (2020) · Physiological Research · doi:10.33549/physiolres.934222 · Cited by 12 · see citing works
The role of MicroRNAs as fine-tuners in the onset of puberty: a comprehensive review
Jeong, H. R., & Hwang, I. T. (2024) · Annals of Pediatric Endocrinology & Metabolism · doi:10.6065/apem.2346238.119 · Cited by 12 · see citing works
MKRN3 circulating levels in girls with central precocious puberty caused by MKRN3 gene mutations
Aiello, F., Palumbo, S., Cirillo, G., Tornese, G., Fava, D., Wasniewska, M. G., Faienza, M. F., Bozzola, M., Luongo, C., Festa, A., et al. (2023) · Journal of Endocrinological Investigation · doi:10.1007/s40618-023-02255-5 · Cited by 10 · see citing works
Circulating makorin ring‐finger protein‐3 ( MKRN 3) levels in healthy men and in men with hypogonadotropic hypogonadism
Varimo, T. J., Hero, M. T., Känsäkoski, J., Vaaralahti, K., Matikainen, N., & Raivio, T. (2015) · Clinical Endocrinology · doi:10.1111/cen.12851 · Cited by 10 · see citing works
Comprehensive Study on Central Precocious Puberty: Molecular and Clinical Analyses in 90 Patients
Narusawa, H., Ogawa, T., Yagasaki, H., Nagasaki, K., Urakawa, T., Saito, T., Soneda, S., Kinjo, S., Sano, S., Mamada, M., et al. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae666 · Cited by 10 · see citing works
Disorders of puberty and neurodevelopment: A shared etiology?
Read, J. E., Vasile‐Tudorache, A., Newsome, A., Lorente, M. J., Agustín‐Pavón, C., & Howard, S. R. (2024) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.15246 · Cited by 10 · see citing works
Six Novel Variants in the MKRN3 Gene Causing Central Precocious Puberty
Gernay, C., Brachet, C., Boros, E., Tenoutasse, S., Libioulle, C., & Heinrichs, C. (2022) · Journal of the Endocrine Society · doi:10.1210/jendso/bvac168 · Cited by 11 · see citing works
MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study
Grandone, A., Cirillo, G., Sasso, M., Tornese, G., Luongo, C., Festa, A., Marzuillo, P., & del Giudice, E. M. (2018) · Hormone Research in Paediatrics · doi:10.1159/000493134 · Cited by 7 · see citing works
MKRN3 circulating levels in Prader–Willi syndrome: a pilot study
Mariani, M., Fintini, D., Cirillo, G., Palumbo, S., del Giudice, E. M., Bocchini, S., Manco, M., Cappa, M., & Grandone, A. (2022) · Journal of Endocrinological Investigation · doi:10.1007/s40618-022-01860-0 · Cited by 8 · see citing works
A novel heterozygous MKRN3 nonsense mutation in a Chinese girl with idiopathic central precocious puberty
Liu, M., Fan, L., & Gong, C. X. (2020) · Medicine · doi:10.1097/md.0000000000022295 · Cited by 8 · see citing works
Genetic regulation in pubertal delay
Howard, S. R. (2019) · Journal of Molecular Endocrinology · doi:10.1530/jme-19-0130 · Cited by 6 · see citing works
Comparison of Makorin Ring Finger Protein 3 Levels Between Obese and Normal Weight Patients with Central Precocious Puberty
Eren, S. E., & Şimşek, E. (2023) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2023.2022-6-6 · Cited by 6 · see citing works
Makorin rings the kisspeptin bell to signal pubertal initiation
Abbara, A., & Dhillo, W. S. (2020) · Journal of Clinical Investigation · doi:10.1172/jci139586 · Cited by 5 · see citing works
Serum level of NPTX1 is independent of serum MKRN3 in central precocious puberty
Jeong, H. R., Yoon, J. S., Lee, H. J., Shim, Y. S., Kang, M. J., & Hwang, I. T. (2020) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2020-0402 · Cited by 5 · see citing works
Genetic etiologies of central precocious puberty
Lee, H. S. (2021) · Precision and Future Medicine · doi:10.23838/pfm.2021.00107 · Cited by 4 · see citing works
Hypothalamic-Pituitary-Gonadal Axis Disorders Impacting Fertility in Both Sexes and the Potential of Kisspeptin-Based Therapies to Treat Them
Acosta‐Martínez, M. (2023) · Handbook of experimental pharmacology · doi:10.1007/164_2023_666 · Cited by 4 · see citing works
Changes in Circulating Levels of miR-30b During Minipuberty and Puberty in Girls
Albrechtsen, H. M., Saritaş, G., Winge, S. B., Main, A. M., Hagen, C. P., Busch, A. S., Juul, A., Almstrup, K., & Mørup, N. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf489 · Cited by 3 · see citing works
Mouse Testicular Mkrn3 Expression Is Primarily Interstitial, Increases Peripubertally, and Is Responsive to LH/hCG
Pereira, S. A., Oliveira, F. C. B., Naulé, L., Royer, C., Neves, F. A. R., Abreu, A. P., Carroll, R. S., Kaiser, U. B., Coêlho, M. S., & Lofrano‐Porto, A. (2023) · Endocrinology · doi:10.1210/endocr/bqad123 · Cited by 3 · see citing works
A single blood luteinizing hormone level of triptorelin stimulation test can diagnose hypothalamic-pituitary-gonadal axis activation in girls with high body mass index
Zeng, B., Huang, Y., Zhou, Y., Li, Y., Huang, P., Xu, Z., & Ma, Y. (2025) · Frontiers in Pediatrics · doi:10.3389/fped.2025.1629423 · Cited by 2 · see citing works
Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3
Heras, V., Sangiao‐Alvarellos, S., Manfredi-Lozano, M., Sanchez-Tapia, M. J., Ruíz-Pino, F., Roa, J., Lara‐Chica, M., Morrugares, R., Jouy, N., Abreu, A. P., et al. (2020) · Yearbook of pediatric endocrinology · doi:10.1530/ey.17.7.12 · Cited by 2 · see citing works
Novel MKRN3 gene mutation associated with central precocious puberty in a Chinese child: a case report
Wang, J., Li, R., Wang, J., Wu, D., Lei, S.-Q., Sang, Y., & Chang, J. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1491664 · Cited by 2 · see citing works
Pubertad normal. Pubertad precoz y retraso puberal
Bouvattier, C. M. (2017) · EMC - Ginecología-Obstetricia · doi:10.1016/s1283-081x(17)84282-x · Cited by 2 · see citing works
Etiology and treatment of central precocious puberty
Kim, S. Y. (2018) · Journal of Korean Medical Association · doi:10.5124/jkma.2018.61.10.591 · Cited by 2 · see citing works
Effect of Active Immunization Using Gonadotropin-Releasing Hormone 2-Multiple Antigen Peptide with Different Adjuvants on the Reproductive Functions of Male Rats
Si, W. (2019) · Pakistan Veterinary Journal · doi:10.29261/pakvetj/2019.058 · Cited by 2 · see citing works
Polycystic ovary syndrome and idiopathic central precocious puberty: two sides of the same coin?
Cela, E., Tarantino, C., Vincenzi, L., Tenuta, M., Pozza, C., Minnetti, M., & Sbardella, E. (2025) · Endocrine · doi:10.1007/s12020-025-04461-y · Cited by 1 · see citing works
Pubertal delay in patients with paternally derived 15q11.2–q13 duplication syndrome and MKRN3 overexpression
Petrone, D., Palumbo, S., Giacobbe, C., Onore, M. E., Esposito, M., Perrotta, S., del Giudice, E. M., Piluso, G., Nigro, V., Santoro, C., et al. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag385
The role of makorin ring finger protein-3, kisspeptin, and neurokinin B in the physiology of minipuberty
Atay, E., Kılınç, S., Ülfer, G., Yiğitbaşı, T., Çakici, Ç., Turan, M., Ceran, Ö., & Atay, Z. (2021) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2020-0331 · Cited by 1 · see citing works
Pediatric endocrinology: an overview of the last decade
Ibáñez, L., Barouti, K., Markantes, G. Κ., Armeni, A. K., & Georgopoulos, N. A. (2018) · HORMONES · doi:10.1007/s42000-018-0067-8 · Cited by 1 · see citing works
Human Genetics of GnRH Neuron Function
Topaloglu, A. K., & Kotan, L. D. (2018) · Wiley eBooks · doi:10.1002/9781119233275.ch17 · Cited by 1 · see citing works
Puberty 1 Pubertal development and regulation
Abreu, A. P., & Kaiser, U. B. (2016)
Análise de metilação global em pacientes com puberdade precoce central familial
Bessa, D. D. S. (2018) · doi:10.11606/t.5.2018.tde-31102018-120553
Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3
Castellano, J. M., Heras, V., Sangiao‐Alvarellos, S., Manfredi-Lozano, M., Sanchez-Tapia, M. J., Ruíz-Pino, F., Roa, J., Lara‐Chica, M., Morrugares, R., Abreu, A. P., et al. (2019) · Endocrine Abstracts · doi:10.1530/endoabs.63.gp62
Does residual virus replication during successful HAART lead to HIV-1 genetic evolution?
Aquaro, S., Svicher, V., & Perno, C. F. (2006) · PubMed
Central Precocious Puberty in Girls: Diagnosis, Management and Outcome
Jaruratanasirikul, S. (2021) · PSU Medical Journal · doi:10.31584/psumj.2021246082
Normal concentrations of steroids and their regulators in blood
Honour, J. W. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-818124-9.00003-6
Caracterização clínica e genética da puberdade precoce central familial
Tinano, F. R. (2023) · doi:10.11606/t.5.2023.tde-13122023-171541
Investigação dos aspectos metabólicos da puberdade precoce central
Seraphim, C. E. (2024) · doi:10.11606/t.5.2024.tde-19062024-165829
Genetic Investigation of Regulatory Regions of MKRN3 and DLK1 Genes in Children with Central Precocious Puberty
Piovesan, M. R., Macena, L. B., Jorge, A. A. L., Lima‐Valassi, H. P., Canton, A. P. M., Mendonca, B. B., Latronico, A. C., Brito, V. N., & Montenegro, L. R. (2024) · Hormone Research in Paediatrics · doi:10.1159/000543155 · Cited by 2 · see citing works
Global secular trends in timing of puberty
Oerkild, J., Thomsen, C. E., Fritzbøger, A. F. Ø., Edström, P., Vilmann, L. S., Groendahl, V. L. R., Holmboe, S. A., Hagen, C. P., Juul, A., Johannsen, T. H., et al. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-13825-6.00153-9
Predicting MKRN3 and DLK1 Variants Using Serum Levels in Precocious PubertyPreprint
Özturan, E. K., Karaman, V., Gedikbaşı, A., Poyrazoğlu, Ş., Darendelıler, F., Uyguner, Z. O., & Baş, F. (2025) · Research Square · doi:10.21203/rs.3.rs-6646118/v1
The role of MKRN3 gene on central precocious puberty
Burgaç, E., Kotan, L. D., Turan, İ., Kör, Y., & Yüksel, B. (2025) · Çukurova medical journal (Online)/Çukurova medical journal · doi:10.17826/cumj.1659996
Use of serum MKRN3 and DLK1 levels in precocious puberty: association with an MKRN3 pathogenic variant
Özturan, E. K., Karaman, V., Gedikbaşı, A., Poyrazoğlu, Ş., Darendelıler, F., Uyguner, Z. O., & Baş, F. (2026) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188261424161
Spatial control of mRNA translation underlies MKRN3-mediated delay of puberty
Shalev, D., Pnueli, L., Argoetti, A., de Leon, T. B., Golan, G., Polyak, G., Hashimshony, T., Mandel‐Gutfreund, Y., & Melamed, P. (2026) · iScience · doi:10.1016/j.isci.2026.116781

Circulating MKRN3 Levels Decline During Puberty in Healthy Boys
Busch, A. S., Hagen, C. P., Almstrup, K., & Juul, A. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-1488 · Cited by 65 · see citing works
MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study
Grandone, A., Cirillo, G., Sasso, M., Capristo, C., Tornese, G., Marzuillo, P., Luongo, C., Umano, G. R., Festa, A., Coppola, R., et al. (2017) · Endocrine · doi:10.1007/s12020-017-1281-x · Cited by 30 · see citing works
MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study
Grandone, A., Cirillo, G., Sasso, M., Tornese, G., Luongo, C., Festa, A., Marzuillo, P., & del Giudice, E. M. (2018) · Hormone Research in Paediatrics · doi:10.1159/000493134 · Cited by 7 · see citing works
Circulating makorin ring finger protein 3 levels decline in boys before the clinical onset of puberty
Varimo, T. J., Dunkel, L., Vaaralahti, K., Miettinen, P. J., Hero, M. T., & Raivio, T. (2016) · European Journal of Endocrinology · doi:10.1530/eje-15-1193 · Cited by 13 · see citing works
Serum Makorin ring finger protein 3 values for predicting Central precocious puberty in girls
Jeong, H. R., Lee, H. J., Shim, Y. S., Kang, M. J., Yang, S., & Hwang, I. T. (2019) · Gynecological Endocrinology · doi:10.1080/09513590.2019.1576615 · Cited by 12 · see citing works

Authors: Hagen, C. P., Sørensen, K., Mieritz, M. G., Johannsen, T. H., Almstrup, K., & Juul, A.
Affiliations: University of Copenhagen (DK)
Corresponding author: Hagen, Casper P.
ORCID: Hagen, Casper P.
Sørensen, Kaspar
Johannsen, Trine Holm
Almstrup, Kristian
Juul, Anders
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2015-05
Volume: 100
Issue: 5
Pages: 1920-1926
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jc.2014-4462
OpenAlex: W2114009937
Cited by: 86
References: 28
Citations by year: 2026: 3 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 12 · 2019: 13 · 2018: 7 · 2017: 6 · 2016: 10 · 2015: 3
FWCI: 9.89
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Topics: Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords: MKRN3, puberty onset, serum biomarkers, GnRH secretion, gonadotropins, follicle-stimulating hormone, luteinizing hormone, age at menarche, prepubertal girls, breast development
MeSH terms: Adolescent, Child, Child, Preschool, Female, Follicle Stimulating Hormone, Genotype, Humans, Luteinizing Hormone, Longitudinal Studies, Prospective Studies, Puberty, Puberty, Precocious, Ribonucleoproteins, Ubiquitin-Protein Ligases, Healthy Volunteers

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks