Time Course of Central Precocious Puberty Development Caused by an &lt;b&gt;&lt;i&gt;MKRN3&lt;/i&gt;&lt;/b&gt; Gene Mutation: A Prismatic Case

Stecchini, Monica F; Macedo, Delanie B.; Reis, Ana Claudia S.; Abreu, Ana Paula; Moreira, Ayrton Custódio; Castro, Margaret de; Kaiser, Ursula B.; Latrônico, Ana Claudia; Antonini, Sonir Roberto Rauber

doi:10.1159/000447515

Cited by 18 publications

(13 citation statements)

References 19 publications

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“…MKRN3 defects were described in 89 patients (76 girls and 13 boys) with CPP from 17 countries: Argentina [15], Belgium [4], Brazil [4, 5, 15, 16, 31], Bulgaria [20], Cyprus [25, 26], Denmark [28], France [7], Germany [9], Greece [6], Israel [8], Italy [7, 10, 19, 27], Japan [14], Korea [12], Spain [13], Taiwan [29], Turkey [11, 30], and United States of America [4]. Eighty-eight patients harbored mutations in the coding sequence and one exhibited a deletion in the promoter region of the gene.…”

Section: Resultsmentioning

confidence: 99%

“…Younger carriers of MKRN3 mutations identified by family screening before the development of pubertal signs have also been described [7, 11], and their clinical follow-up are still not known. Stecchini et al reported a case of a girl identified as a carrier of MKRN3 mutation at the age of 4 because of a positive family history, who was diagnosed with CPP at the age of 6.7 years [16].…”

Section: Resultsmentioning

confidence: 99%

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MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis

Valadares

Meireles

Toledo

et al. 2019

Journal of the Endocrine Society

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MKRN3 mutations represent the most common genetic cause of central precocious puberty (CPP) but associations between genotype and clinical features have not been extensively explored. This systematic review and meta-analysis investigated genotype-phenotype associations and prevalence of MKRN3 mutations in CPP. The search was conducted in seven electronic databases (Cochrane, EMBASE, LILACS, LIVIVO, PubMed, Scopus, and Web of Science) for articles published until 4 September 2018. Studies evaluating MKRN3 mutations in patients with CPP were considered eligible. A total of 22 studies, studying 880 subjects with CPP, fulfilled the inclusion criteria. Eighty-nine subjects (76 girls) were identified as harboring MKRN3 mutations. Girls, compared with boys, exhibited earlier age at pubertal onset (median, 6.0 years; range, 3.0 to 7.0 vs 8.5 years; range, 5.9 to 9.0; P < 0.001), and higher basal FSH levels (median, 4.3 IU/L; range, 0.7 to 13.94 IU/L vs 2.45 IU/L; range, 0.8 to 13.70 IU/L; P = 0.003), and bone age advancement ( Δ BA; median, 2.3 years; range, −0.9 to 5.2 vs 1.2 years; range, 0.0 to 2.3; P = 0.01). Additional dysmorphisms were uncommon. A total of 14 studies evaluating 857 patients were included for quantitative analysis, with a pooled overall mutation prevalence of 9.0% (95% CI, 0.04 to 0.15). Subgroup analysis showed that prevalence estimates were higher in males, familial cases, and in non-Asian countries. In conclusion, MKRN3 mutations are associated with nonsyndromic CPP and manifest in a sex-dimorphic manner, with girls being affected earlier. They represent a common cause of CPP in western countries, especially in boys and familial cases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis

Valadares

Meireles

Toledo

et al. 2019

Journal of the Endocrine Society

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“…2A), was reported in 2013 as the first gene in which loss-of-function mutations were associated with CPP, with variants initially identified by exome sequencing in five families (27). Multiple novel variants, including frameshift, nonsense, and missense mutations, in MKRN3 across various families, ethnicities and geographical regions have now been reported (27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50). Mutations in MKRN3 are now the most common known genetic etiology of CPP and are more common in familial CPP (33-46% of cases) compared to sporadic CPP (3.9% of cases) (28).…”

Section: Mkrn3mentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes

Roberts

Kaiser

2020

European Journal of Endocrinology

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Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3), a maternally imprinted gene on chromosome 15 within the Prader-Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.

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“…18 Subsequently, mutations in MKRN3 have been described in many additional patients with CPP throughout the world. [21][22][23][24][25][26][27][28][29][30][31][32] For a recent systematic review and meta-analysis of the MKRN3 mutations identified in patients with CPP to date, see the study by Valadares et al 33 Precocious puberty is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys, which corresponds to 2.5 to 3 standard deviations below the mean age of puberty onset, as defined by population studies. 34 Early age of puberty has been associated with many deleterious health effects such as cancer, cardiovascular disease, and metabolic and behavioral disorders.…”

Section: Mkrn3 Mutations In Central Precocious Pubertymentioning

confidence: 99%

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

Naulé

Kaiser

2019

Semin Reprod Med

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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.

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Time Course of Central Precocious Puberty Development Caused by an <b><i>MKRN3</i></b> Gene Mutation: A Prismatic Case

Cited by 18 publications

References 19 publications

MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis

MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis

GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes

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

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