Investigation of MKRN3 Mutation in Patients with Familial Central Precocious Puberty

Aycan, Zehra; Savaş‐Erdeve, Şenay; Çeti̇nkaya, Semra; Kurnaz, Erdal; Keskin, Mahmut; Şahin, Nursel; Bayramoğlu, Elvan; Ceylaner, Gülay

doi:10.4274/jcrpe.5506

Cited by 24 publications

(16 citation statements)

References 25 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%

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%

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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“…Furthermore, two recent studies have revealed a negative correlation between circulating MKRN3 levels and the Tanner stages of puberty in healthy children and adolescents [27,28]. Therefore, screening is recommended, in particular for MKRN3 mutations, for all patients with familial ICPP, patients with unclear family histories [3] and patients with sporadic CPP [2]. It is also important that the younger siblings of patients with familial CPP secondary to MKRN3 mutations be screened for the same mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Despite efforts to establish the genetic mechanism underlying normal and precocious pubertal timing in humans, it remains largely unknown [2]. However, gain-of-function mutations in the KISS1 and KISSR1 (previously named GPR54) genes and loss-of-function mutations in the makorin ring finger protein 3 (MKRN3) gene were shown to lead to CPP [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

MKRN3 and KISS1R mutations in precocious and early puberty

et al. 2020

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Background: Pubertal timing is known to be influenced by interactions among various genetic, nutritional, environmental and socioeconomic factors, although the ultimate mechanisms underlying the increase in pulsatile GnRH secretion at puberty have yet to be fully elucidated. The aim of our research was to verify the role of KISSR1 (previously named GPR54) and MKRN3 genes on pubertal timing. Methods: We analyzed the DNA sequence of these genes in 13 girls affected by central precocious puberty (CPP) who showed onset of puberty before 8 years of age, and in 6 girls affected by early puberty (EP) between 8 and 10 years of age. Results: Direct sequencing of the KISS1R (GPR54) gene revealed two SNPs. One SNP is a missense variant (rs 350,132) that has been previously reported in connection to CPP in Korean girls. The other variant that we found in the GPR54 gene (rs764046557) was a missense SNP located in exon 5 at position 209 of the aminoacid. We identified this variant in only one CPP patient. Automatic sequencing of MKRN3 in all patients revealed three variants in eight subjects. In 6 out of 19 (31.5%) patients (3/13 CPP patients and 3/6 EP patients) we found the synonymous variant c.663C > T (rs2239669). Another synonymous variant (rs140467331) was found in one of our CPP patients, as well as one missense variant (rs760981395) in another CPP patient. Conclusion: In conclusion, we identified sequence variations of the KISS1R and MKRN3 genes, two of the most frequent genetic causes of ICPP. Our results suggest that these variants might be inducible factors in the pathogenesis of CPP.

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“…In girls, CPP is most commonly deemed idiopathic, for which no identifiable cause is identified (24). However, emerging genetic causes of CPP, especially mutations in Makorin Ring Finger Protein 3 (MKRN3) are increasingly being identified in cases previously deemed idiopathic (27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50). While CPP less commonly affects boys, when it does occur, it is more likely to have an identifiable pathologic cause, such as a hypothalamic hamartoma (24).…”

Section: Central Precocious Pubertymentioning

confidence: 99%

“…Serum levels of MKRN3 have also been shown to be lower in girls with CPP compared to agematched controls and comparable to children matched for pubertal stage (76,77). It would be of interest to validate the MKRN3 assay used in patients expected to have negligible MKRN3 protein synthesis, such as those with frameshift or nonsense mutations, or patients with Prader-Willi syndrome (27,29).…”

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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Investigation of MKRN3 Mutation in Patients with Familial Central Precocious Puberty

Cited by 24 publications

References 25 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

MKRN3 and KISS1R mutations in precocious and early puberty

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

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