Central Precocious Puberty in a Girl and Early Puberty in Her Brother Caused by a Novel Mutation in the MKRN3 Gene

Settas, Nikolaos; Dacou-Voutetakis, Catherine; Karantza, Maria; Kanaka‐Gantenbein, Christina; Chrousos, George P.; Voutetakis, Antonis

doi:10.1210/jc.2013-4084

Cited by 74 publications

(94 citation statements)

References 18 publications

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“…These mutations were found in 15 patients from five families. Thirteen other patients with iCPP and MKRN3 mutations, from six families, have since been described (12,13,14,15). In our study, heterozygous MKRN3 mutations were found in 14 of 46 index patients with iCPP (30%).…”

Section: Discussionsupporting

confidence: 55%

“…This may reflect a recruitment bias and the well-known higher prevalence of precocious puberty in girls than in boys. No accurate information about age at puberty onset was available for three previously reported cases of iCPP in male patients with MKRN3 mutations (11,12,13). The other five boys had a median age at Tanner stage 2 of 8.25 years (8-8.5), suggesting that the decrease in age at puberty onset was smaller for boys than for girls.…”

Section: Discussionmentioning

confidence: 97%

“…The mutation was inherited from the father in all 15 cases, consistent with the maternal imprinting of MKRN3. Other loss-of-function MKRN3 mutations have since been reported (12,13,14,15). MKRN3, located on chromosome 15q11.2, in the critical region for Prader-Willi syndrome, encodes MKRN3 protein.…”

Section: Introductionmentioning

confidence: 99%

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Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

Simon

Mekhail

et al. 2016

European Journal of Endocrinology

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Context and objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamicpituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations. Design: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients. Results: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), PZ0.01). Conclusions: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 97%

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Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

Simon

Mekhail

et al. 2016

European Journal of Endocrinology

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“…Although ICPP is typically inherited from mother to daughter and affects mostly girls (12), mutations in MKRN3 seem to be equally distributed among males and females, although the effect on females seems to be somewhat stronger (3,6). In our family, the girl's age at the onset of puberty was comparable to previous reports in female MKRN3 mutation carriers (range: 3.0-6.5 y; mean 5.9; median 6.0 y) (13).…”

Section: Discussionmentioning

confidence: 98%

“…The p.Arg345His mutation identified in this study is situated in the C3HC4 RING domain of MKRN3 responsible for ubiquitin ligase activity of the protein. Two of the four previously reported missense mutations in ICPP patients (p.Arg365Ser and p.Cys340Gly) are situated in this same domain (3,6), but the functional consequences of these mutations, although predicted to be deleterious and disrupt the tertiary protein structure (6), have not been confirmed. The two other reported missense mutations, p.Phe417Ile and p.His420Gln, are located in the third RNA-binding C3H zinc-finger domain and are also predicted to have deleterious effects (7,9).…”

Section: Discussionmentioning

confidence: 99%

A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty

et al. 2015

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The tempo of human childhood: a maternal foot on the accelerator, a paternal foot on the brake

Kotler¹,

Haig

2018

Evolutionary Anthropology

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Relative to the life history of other great apes, that of humans is characterized by early weaning and short interbirth intervals (IBIs). We propose that in modern humans, birth until adrenarche, or the rise in adrenal androgens, developmentally corresponds to the period from birth until weaning in great apes and ancestral hominins. According to this hypothesis, humans achieved short IBIs by subdividing ancestral infancy into a nurseling phase, during which offspring fed at the breast, and a weanling phase, during which offspring fed specially prepared foods. Imprinted genes influence the timing of human weaning and adrenarche, with paternally expressed genes promoting delays in childhood maturation and maternally expressed genes promoting accelerated maturation. These observations suggest that the tempo of human development has been shaped by consequences for the fitness of kin, with faster development increasing maternal fitness at a cost to child fitness. The effects of imprinted genes suggest that the duration of the juvenile period (adrenarche until puberty) has also been shaped by evolutionary conflicts within the family.

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Central Precocious Puberty in a Girl and Early Puberty in Her Brother Caused by a Novel Mutation in the MKRN3 Gene

Cited by 74 publications

References 18 publications

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty

The tempo of human childhood: a maternal foot on the accelerator, a paternal foot on the brake

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