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  • 1
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 4, No. Supplement_1 ( 2020-05-08)
    Abstract: Context: Loss-of-function mutations in the maternally imprinted Makorin RING-finger 3 (MKRN3) gene (15q11.2) are the most prevalent cause of familial central precocious puberty (CPP). Objectives: To analyze the phenotypes of a large cohort of children with CPP due to MKRN3 mutations and to compare them with the phenotypes of idiopathic CPP. Setting and Participants: We studied 73 individuals from 37 families with mutations in MKRN3 originating from nine different countries. The phenotypes of these patients at initial diagnosis were compared to a cohort of 124 patients with idiopathic CPP. Additionally, expression of nine different genes implicated with pubertal timing, including MKRN3, was performed in the hypothalamus of female mice in different phases of sexual maturation. Results: Nineteen different heterozygous, paternally inherited mutations in MKRN3 were identified in 73 patients with CPP (48 girls and 25 boys). Six MKRN3 mutations were frameshifts, one introduced a premature stop codon, 11 were missense mutations predicted to be pathogenic, and one was a deletion in the promoter region. A frameshift mutation affecting codon 161 in the amino terminal region of the protein was the most frequent MKRN3 defect (46%), representing a hotspot region. Among the cohort with MKRN3 mutations, first pubertal signs occurred at 6·2 ± 1·2 years in girls and 7·6 ± 1·4 years in boys. Patients harboring severe frameshift/nonsense mutations did not differ significantly in any clinical or hormonal parameters compared to the 20 patients with missense variants. However, when the 48 girls with MKRN3 mutations were compared with 124 idiopathic CPP girls, some parameters could be considered as possible predictors of the genetic cause: a lower age at first medical appointment (7·1 ± 1·1 in the MKRN3 group vs. 8·0 ± 2 years in the idiopathic group; p & lt; 0.001) and a shorter time interval between puberty onset and medical assistance (0·8 ± 0·8 vs 2·2 ± 2·1 years; p & lt; 0.001). Interestingly, the other predictor of MKRN3 mutations was a higher basal FSH level (5·1 ± 2·3 vs 3·9 ± 2·7 IU/L; p = 0.017) at first evaluation, although no cutoff value yielded good accuracy. Patients originating from European/Mediterranean countries were more likely to have missense variants (56% of all mutations) than North American and South American (23%) counterparts (p & lt;0.001). Mouse Mkrn3 mRNA levels in the arcuate nucleus were highest in the prepubertal phase when compared with expression of other genes and Mkrn3 decreased progressively through puberty and adult ages. Conclusions: Different types of loss-of-function MKRN3 mutations were associated with premature sexual development in both sexes. Their phenotypes were relatively uniform, regardless of the mutation type. Clinical features of children with MKRN3 mutations were similar to the idiopathic CPP group.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2020
    detail.hit.zdb_id: 2881023-5
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  • 2
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 106, No. 4 ( 2021-03-25), p. e1041-e1050
    Abstract: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). Objective To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. Methods Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. Results Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. Conclusion Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
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    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2021
    detail.hit.zdb_id: 2026217-6
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