Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
J Clin Endocrinol Metab. 2021 Mar 25;106(4):1041-1050. doi: 10.1210/clinem/dgaa955.
Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP).
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.
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.
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.
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.
makorin RING 手指蛋白 3（MKRN3）的功能丧失性突变是家族性中枢性性早熟（CPP）最常见的单基因病因。
描述因 MKRN3 突变导致 CPP 的大样本队列患者的临床和激素特征，并比较不同类型遗传缺陷的特征。
对 716 例家族性或特发性 CPP 患者进行 MKRN3 突变的 Sanger 测序筛查，使用 156 例巴西特发性 CPP（ICPP）女孩作为对照组。
71 例患者（36 个家系的 45 名女孩和 26 名男孩）存在 18 种不同的功能丧失性 MKRN3 突变。8 种突变被归类为严重型（70%的患者）。71 例患者中，女孩的初潮征象出现在 6.2±1.2 岁，男孩出现在 7.1±1.5 岁。与 ICPP 相比，MKRN3 突变患者的青春期开始与首次评估之间的时间间隔更短，且卵泡刺激素水平更高。严重型 MKRN3 突变患者的骨龄进展大于错义突变患者（2.3±1.6 比 1.6±1.4 岁，P=0.048），且初诊时基础黄体生成素水平更高（2.2±1.8 比 1.1±1.1 UI/L，P=0.018）。计算蛋白质建模显示，60%的错义突变被预测会导致蛋白质失稳。
由 MKRN3 功能丧失性突变引起的生殖轴遗传性过早激活在临床上与 ICPP 无法区分。然而，遗传缺陷的类型可能会影响骨龄成熟度和促性腺激素水平。
