Males with Paternally Inherited MKRN3 Mutations May Be Asymptomatic

Dimitrova-Mladenova, Mihaela; Stefanova, Elisaveta; Glushkova, Maria; Тодорова, Албена; Todorov, Tihomir; Константинова, М. М.; Kazakova, Krasimira; Tincheva, Radka

doi:10.1016/j.jpeds.2016.08.065

Cited by 17 publications

(12 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Several other loss of function mutations in MKRN3 have successively been described, making MKRN3 defects the most frequent genetic cause of CPP reported until now [5][6][7][8][9][10][11][12][13][14][15][16][17]. However, the exact prevalence of mutations in CPP patients is not known.…”

Section: Introductionmentioning

confidence: 99%

Molecular Screening of MKRN3, DLK1, and KCNK9 Genes in Girls with Idiopathic Central Precocious Puberty

et al. 2017

View full text Add to dashboard Cite

Background: Mutations in the imprinted gene MKRN3 have been described as a common genetic cause of idiopathic central precocious puberty (CPP), in particular in familial cases. However, the exact prevalence of mutations is unknown. Single nucleotide polymorphisms in 2 other imprinted genes, DLK1 and KCNK9, have been associated with age at menarche. We investigated the prevalence of mutations in MKRN3, DLK1, and KCNK9 genes in a cohort of girls with idiopathic CPP. Methods: MKRN3, DLK1, and KCNK9 coding regions were sequenced in 60 girls with idiopathic CPP (familial in 23 cases). Results: Three mutations, including a new one, in MKRN3 were found in 2 familial cases (c.1229G>A; p.Cys410Ter and c.477_485del; p.Pro160Cysfs*14) (8.7%) and in 1 sporadic case (c.982C>T; p.Arg328Cys) (2.8%). We did not find rare variants in DLK1 and KCNK9 genes. Conclusions: (1) The prevalence of MKRN3 mutations in our cohort was similar to that reported in the literature in sporadic cases but lower than previously described in familial ones. This could be due to different inheritance patterns of families studied; (2) we expanded the phenotype of MKRN3 defects describing 3 more patients with MKRN3 mutations; and (3) point mutations in DLK1 and KCNK9 at least do not seem to be a common cause of CPP in girls.

show abstract

“…Currently, MKRN3 mutations are recognized as the main genetic cause of CPP and appear to be particularly common in familial cases (up to 33% to 46%) [7, 18], although no mutations were described in the subgroup of Korean girls with familial CPP [12]. In the sporadic form of CPP, the prevalence was 3.9% in a large cohort of Brazilian girls [5], however it was variable in other reports, ranging from 0% to 20% in small cohorts of Italian and Bulgarian girls, respectively [19, 20]. Thus, the exact prevalence of mutations in patients with CPP and possible geographical differences worldwide has not been explored.…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

Males with Paternally Inherited MKRN3 Mutations May Be Asymptomatic

Cited by 17 publications

References 13 publications

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

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

Molecular Screening of MKRN3, DLK1, and KCNK9 Genes in Girls with Idiopathic Central Precocious Puberty

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

Contact Info

Product

Resources

About