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Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3
Open accessAbstract
BACKGROUND: The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS: We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS: We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS: Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).
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In the citing paper
“The first gene with an inhibitory effect on GnRH secretion with mutations identified in human beings was MKRN3 (table, figure 2).”
From Pubertal development and regulation (2016) · cites this paper as [52]
In the citing paper
“The identification of this novel factor in the GnRH network arose from whole-exome sequencing analysis of families with central precocious puberty.52”
From Pubertal development and regulation (2016) · cites this paper as [52]
In the citing paper
“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 [52]
In the citing paper
“MKRN3 expression in the arcuate nucleus of mice is high prepubertally and decreases before puberty initiation, reaching very low levels in adult life.52”
From Pubertal development and regulation (2016) · cites this paper as [52]
In the citing paper
“Following this inheritance pattern, all MKRN3 mutations identified in patients with central precocious puberty were inherited from their fathers.52”
From Pubertal development and regulation (2016) · cites this paper as [52]
In the citing paper
“More recently, genetic studies have led to the identification of the most common known genetic cause of central precocious puberty, MKRN3.52”
From Pubertal development and regulation (2016) · cites this paper as [52]
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Cites
RADIOGRAPHIC ATLAS OF SKELETAL DEVELOPMENT OF THE HAND AND WRIST
GREULICH, W. W., & Pyle, S. I. (1959) · The American Journal of the Medical Sciences · doi:10.1097/00000441-195909000-00030 · Cited by 5,562
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
Self-citationHypogonadotropic 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
Parent, A.-S., Teilmann, G., Juul, A., Skakkebaek, N. E., Toppari, J., & Bourguignon, J.-P. (2003) · Endocrine Reviews · doi:10.1210/er.2002-0019 · Cited by 1,762
Cassidy, S. B., Schwartz, S., Miller, J. L., & Driscoll, D. J. (2012) · Genetics in Medicine · doi:10.1038/gim.0b013e31822bead0 · Cited by 1,452
Navarro, V. M., Gottsch, M. L., Chavkin, C., Okamura, H., Clifton, D. K., & Steiner, R. A. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.1569-09.2009 · Cited by 779
Self-citationNeurobiological Mechanisms of the Onset of Puberty in Primates
Terasawa, E., & Fernandez, D. L. (2001) · Endocrine Reviews · doi:10.1210/edrv.22.1.0418 · Cited by 573
A GPR54 -Activating Mutation in a Patient with Central Precocious Puberty
Teles, M. G., Bianco, S. D. C., Brito, V. N., Trarbach, E. B., Kuohung, W., Xu, S., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., & Latronico, A. C. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa073443 · Cited by 572
Self-citationThirty 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
Public health implications of altered puberty timing
Golub, M. S., Collman, G. W., Foster, P. M. D., Kimmel, C. A., Rajpert-De Meyts, E., Reiter, E. O., Sharpe, R. M., Skakkebaek, N. E., & Toppari, J. (2008) · PEDIATRICS · doi:10.1542/peds.2007-1813g · Cited by 497
Mutations of the KISS1 gene in disorders of puberty
Silveira, L. G., Noel, S. D., Silveira-Neto, A. P., Abreu, A. P., Brito, V. N., Santos, M. G., Bianco, S. D. C., Kuohung, W., Xu, S., Gryngarten, M., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2421 · Cited by 352
Self-citationThe genetic and molecular basis of idiopathic hypogonadotropic hypogonadism
Bianco, S. D. C., & Kaiser, U. B. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.177 · Cited by 336
Self-citationZhu, H., Shah, S. P., Shyh‐Chang, N., Shinoda, G., Einhorn, W. S., Viswanathan, S. R., Takeuchi, A., Grasemann, C., Rinn, J. L., Lopez, M. F., et al. (2010) · Nature Genetics · doi:10.1038/ng.593 · Cited by 310
Self-citationVariation in the Timing of Puberty: Clinical Spectrum and Genetic Investigation
Palmert, M. R., & Boepple, P. A. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.6.7603 · Cited by 304
Normal ranges for immunochemiluminometric gonadotropin assays
Neely, E. K., Hintz, R. L., Wilson, D. M., Lee, P. A., Gautier, T., Argente, J., & Stene, M. A. (1995) · The Journal of Pediatrics · doi:10.1016/s0022-3476(95)70254-7 · Cited by 256
Neurobiological Mechanisms of the Onset of Puberty in Primates
Terasawa, E. (2001) · Endocrine Reviews · doi:10.1210/er.22.1.111 · Cited by 253
Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat
Navarro, V. M., Castellano, J. M., McConkey, S. M., Pineda, R., Ruíz-Pino, F., Pinilla, L., Clifton, D. K., Tena‐Sempere, M., & Steiner, R. A. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00517.2010 · Cited by 251
Self-citationJong, 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
Familial central precocious puberty suggests autosomal dominant inheritance
de Vries, L., Kauschansky, A., Shohat, M., & Phillip, M. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030361 · Cited by 195
Neurobiological mechanisms of puberty in higher primates
Plant, T. M. (2004) · Human Reproduction Update · doi:10.1093/humupd/dmh001 · Cited by 188
Lucas, F. A. S., Wang, G. T., Scheet, P. A., & Peng, B. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr667 · Cited by 140
Genetic approaches to stature, pubertal timing, and other complex traits
Palmert, M. R., & Hirschhorn, J. N. (2003) · Molecular Genetics and Metabolism · doi:10.1016/s1096-7192(03)00107-0 · Cited by 135
Self-citationA paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader–Willi syndrome
Kanber, D., Giltay, J. C., Wieczorek, D., Zogel, C., Hochstenbach, R., Caliebe, A., Kuechler, A., Horsthemke, B., & Buiting, K. (2008) · European Journal of Human Genetics · doi:10.1038/ejhg.2008.232 · Cited by 134
The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions
Semple, R. K., & Topaloglu, A. K. (2010) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03687.x · Cited by 117
Intra-pair similarity in physical growth of monozygotic and of dizygotic twins during puberty
Fischbein, S. (1977) · Annals of Human Biology · doi:10.1080/03014467700002401 · Cited by 113
Gray, T. A., Hernandez, L., Carey, A. H., Schaldach, M. A., Smithwick, M. J., Rus, K., Marshall Graves, J. A., Stewart, C. L., & Nicholls, R. D. (2000) · Genomics · doi:10.1006/geno.2000.6199 · Cited by 108
What controls the timing of puberty? An update on progress from genetic investigation
Gajdos, Z. K. Z., Hirschhorn, J. N., & Palmert, M. R. (2009) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e328320253c · Cited by 95
Self-citationGill, J. C., Navarro, V. M., Kwong, C., Noel, S. D., Martin, C., Xu, S., Clifton, D. K., Carroll, R. S., Steiner, R. A., & Kaiser, U. B. (2012) · Endocrinology · doi:10.1210/en.2012-1529 · Cited by 90
Self-citationPrevalence of Decreased Visual Acuity among Preschool-Aged Children in an American Urban Population
Friedman, D. S., Repka, M. X., Katz, J., Giordano, L., Ibironke, J. O., Hawes, P., Burkom, D., & Tielsch, J. M. (2008) · Ophthalmology · doi:10.1016/j.ophtha.2008.04.006 · Cited by 82
Gill, J. C., Wang, O., Kakar, S., Martinelli, E., Carroll, R. S., & Kaiser, U. B. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011911 · Cited by 79
Self-citationGPR54 Polymorphisms in Chinese Girls with Central Precocious Puberty
Luan, X., Yu, H., Wei, X., Zhou, Y., Wang, W., Li, P., Gan, X., Wei, D., & Xiao, J. (2007) · Neuroendocrinology · doi:10.1159/000107511 · Cited by 61
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 53
Parent, A., Matagne, V., Westphal, M., Heger, S., Ojeda, S. R., & Jung, H. (2007) · Hormone Research in Paediatrics · doi:10.1159/000111815 · Cited by 44
NAKAYAMA, Y., Wondisford, F. E., Lash, R. W., Bale, A. E., Weintraub, B. D., Cutler, G. B., & Radovick, S. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-70-5-1233 · Cited by 43
The Rate of Growth and Maturing of Twins
Skład, M. (1977) · Acta geneticae medicae et gemellologiae · doi:10.1017/s0001566000009703 · Cited by 37
Dauber, A. N., Stoler, J. M., Hechter, E., Safer, J., & Hirschhorn, J. N. (2012) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2012.07.055 · Cited by 35
Self-citationFreitas, K. C. M., Ryan, G. L., Brito, V. N., Tao, Y., Costa, E. M. F., Mendonca, B. B., Segaloff, D. L., & Latronico, A. C. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.07.1519 · Cited by 24
Self-citationZhao, Y., Chen, T., Zhou, Y., Li, K., & Xiao, J. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.09.049 · Cited by 13
Novel paternally expressed intergenic transcripts at the mouse Prader–Willi/Angelman Syndrome locus
Buettner, V. L., Walker, A. M., & Singer–Sam, J. (2005) · Mammalian Genome · doi:10.1007/s00335-004-2452-7 · Cited by 11
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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
Self-citationParent-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
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Latronico, A. C., Brito, V. N., & Carel, J. (2016) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00380-0 · Cited by 538
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Metadata
- Authors
- 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., Rodrigues, T., Kochi, C., Longui, C. A., Beckers, D., de Zegher, F., Montenegro, L. R., Mendonca, B. B., Carroll, R. S., Hirschhorn, J. N., Latronico, A. C., & Kaiser, U. B.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Universidade de São Paulo (BR)
- Nemours Children’s Clinic (US)
- Hospital das Clínicas da Universidade Federal de Minas Gerais (BR)
- Faculdade de Ciências Médicas da Santa Casa de São Paulo (BR)
- Universitair Ziekenhuis Leuven (BE)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2013-06-27
- Volume
- 368
- Issue
- 26
- Pages
- 2467-2475
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3808195
- OpenAlex
- W1981122661
- Cited by
- 534
- References
- 38
- Citations by year
- 2026: 30 · 2025: 31 · 2024: 33 · 2023: 36 · 2022: 42 · 2021: 43 · 2020: 56 · 2019: 41 · 2018: 45 · 2017: 35 · 2016: 46 · 2015: 54 · 2014: 36 · 2013: 5
- FWCI
- 56.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007529)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F05HD072773, R00HD071970, K12HD051959, K23HD073351, K99HD071970, R21HD066495, P30HD018655, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- central precocious puberty, MKRN3, genomic imprinting, chromosome 15q11-q13, paternally expressed genes, frameshift mutation, missense mutations, hypothalamic-pituitary-gonadal axis, GnRH pulsatility, arcuate nucleus
- MeSH terms
- Animals, Arcuate Nucleus of Hypothalamus, Child, Child, Preschool, Female, Heterozygote, Humans, Hypothalamus, Male, Pedigree, Puberty, Precocious, Ribonucleoproteins, RNA, Messenger, Frameshift Mutation, Sequence Analysis, DNA, Mutation, Missense, Ubiquitin-Protein Ligases, Mice, Genetic Association Studies, Exome
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