Endocrinology Unit, University Pediatric Department, Bambino Gesù Children's Hospital, Piazza S.Onofrio, 4, 00165, Rome, Italy.
Department of Woman, Child, General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
J Endocrinol Invest. 2022 Nov;45(11):2165-2170. doi: 10.1007/s40618-022-01860-0. Epub 2022 Jul 19.
Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on 15q11.2-q13 region, encodes makorin ring finger protein 3, whose deficiency causes precocious puberty, an extremely rare symptom in PWS.
This study aimed to evaluate MKRN3 levels in patients with PWS and to analyze its correlation with sexual hormone levels, insulin resistance and Body Mass Index (BMI).
We performed an observational cross-sectional study and enrolled 80 patients with genetically confirmed diagnosis of PWS with median age of 9.6 years.
MKRN3 levels were measurable in 49 PWS patients with a geometric mean of 34.9 ± 22 pg/ml (median: 28.4). Unmeasurable levels of MKRN3 were found in 31 patients. No statistically significant differences were found between patients with and without measurable MKRN3 levels for any clinical, biochemical, or genetic characteristics. However, MKRN3 levels were inversely correlated with HOMA-IR index (p: 0.005) and HbA1c (p: 0.046) values. No statistically significant correlations were found between MKRN3 and LH, estradiol and testosterone concentrations, pubertal development and genetic defect, whereas a direct correlation with FSH was found (p: 0.007).
The typical genetic defect of PWS should lead to unmeasurable levels of the MKRN3 protein due to the inactivation of the paternal allele. Measurable circulating MKRN3 could suggest the possible involvement of tissue-specific imprinting mechanisms and other regulatory factors in gene expression. Correlations with HOMA-IR index, HbA1c, and FSH suggest peripheral actions of MKRN3, but future studies are warranted to investigate this topic.
普拉德-威利综合征（PWS）中的性腺功能减退症通常归因于下丘脑功能障碍或原发性性腺缺陷。MKRN3 是位于 15q11.2-q13 区域的母源印记基因，编码 makorin 环指蛋白 3，其缺乏导致性早熟，这是 PWS 极为罕见的症状。
本研究旨在评估 PWS 患者的 MKRN3 水平，并分析其与性激素水平、胰岛素抵抗和体重指数（BMI）的相关性。
我们进行了一项观察性横断面研究，纳入了 80 名经基因证实的 PWS 患者，中位年龄为 9.6 岁。
49 名 PWS 患者的 MKRN3 水平可测量，几何均数为 34.9±22pg/ml（中位数：28.4）。31 名患者的 MKRN3 水平不可测量。MKRN3 可测量与不可测量水平的患者在任何临床、生化或遗传特征方面均无统计学差异。然而，MKRN3 水平与 HOMA-IR 指数（p：0.005）和 HbA1c（p：0.046）值呈负相关。MKRN3 与 LH、雌二醇和睾酮浓度、青春期发育和遗传缺陷之间无统计学显著相关性，而与 FSH 呈直接相关性（p：0.007）。
PWS 的典型遗传缺陷应导致 MKRN3 蛋白的不可测量水平，这是由于父本等位基因的失活。可测量的循环 MKRN3 可能提示组织特异性印记机制和其他调节因子参与基因表达。与 HOMA-IR 指数、HbA1c 和 FSH 的相关性提示 MKRN3 的外周作用，但需要进一步的研究来探讨这一课题。
