De Toni Luca, Di Nisio Andrea, Speltra Elena, Rocca Maria Santa, Ghezzi Marco, Zuccarello Daniela, Turiaco Nunzio, Ferlin Alberto, Foresta Carlo
Department of Medicine (L.D.T., A.D.N., E.S., M.S.R., M.G., A.F., C.F.), Unit of Andrology and Reproductive Medicine, University of Padova, 35128 Padova, Italy; Clinical Genetics Unit (D.Z.), Department of Woman and Child Health, University of Padova, 35128 Padova, Italy; and Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences (N.T.), University of Messina, 98124 Messina, Italy.
J Clin Endocrinol Metab. 2016 Mar;101(3):953-61. doi: 10.1210/jc.2015-3967. Epub 2016 Jan 6.
The G protein-coupled receptor GPRC6A is an emerging effector with multiple endocrine roles, including stimulation of T production from the testis. Recently, two men with an inactivating mutation (F464Y) of GPRC6A have been identified, and they showed primary testicular failure and deranged spermatogenesis. Furthermore, one of them also reported cryptorchidism at birth. In addition, a polymorphism (rs2274911, Pro91Ser) in GPRC6A is associated with prostate cancer, a typical androgen-sensitive cancer.
To study the possible association between rs2274911 polymorphism and male fertility and/or cryptorchidism. Design, Patients, Settings: A total of 611 subjects, including 343 infertile patients, 197 normozoospermic controls, and 71 cryptorchid newborns, were retrospectively selected.
Sequencing analysis for rs2274911 polymorphism and F464Y mutation, and serum levels of FSH, LH, and T were assessed. In vitro functional studies for rs2274911 and F464Y were also performed.
Homozygous subjects for the risk allele A of rs2274911 had a 4.60-fold increased risk of oligozoospermia and 3.52-fold increased risk of cryptorchidism. A significant trend for increased levels of LH in the GA and AA genotypes, compared with GG homozygotes, was detected in men with azoospermia/cryptozoospermia (P for trend = .027), further supporting an association with primary testicular failure. The mutation F464Y was found in one cryptorchid child (one in 71; 1.41%). Functional studies showed that the A allele of rs2274911 and the F464Y substitution were associated with lower exposition of the receptor on the cell membrane and a reduced downstream phosphorylation of ERK1/2 with respect to wild type.
Our results suggest that GPRC6A inactivation or sub-function contributes to reduced exposure to androgens, leading to cryptorchidism during fetal life and/or low sperm production in adulthood.
G蛋白偶联受体GPRC6A是一种新出现的具有多种内分泌作用的效应分子，包括刺激睾丸产生睾酮。最近，已鉴定出两名携带GPRC6A失活突变（F464Y）的男性，他们表现出原发性睾丸功能衰竭和精子发生紊乱。此外，其中一人还报告出生时患有隐睾症。另外，GPRC6A中的一种多态性（rs2274911，Pro91Ser）与前列腺癌（一种典型的雄激素敏感性癌症）相关。
研究rs2274911多态性与男性生育力和/或隐睾症之间可能存在的关联。设计、患者、研究环境：回顾性选取了总共611名受试者，包括343名不育患者、197名正常精子症对照者和71名隐睾新生儿。
对rs2274911多态性和F464Y突变进行测序分析，并评估血清促卵泡激素（FSH）、促黄体生成素（LH）和睾酮（T）水平。还对rs2274911和F464Y进行了体外功能研究。
rs2274911风险等位基因A的纯合子受试者少精子症风险增加4.60倍，隐睾症风险增加3.52倍。在无精子症/隐匿精子症男性中，与GG纯合子相比，GA和AA基因型的LH水平有显著升高趋势（趋势P值 = 0.027），进一步支持与原发性睾丸功能衰竭有关联。在一名隐睾儿童中发现了F464Y突变（71例中有1例；1.41%）。功能研究表明，rs2274911的A等位基因和F464Y替代与细胞膜上受体的暴露减少以及相对于野生型ERK1/2下游磷酸化减少有关。
我们的结果表明，GPRC6A失活或功能减退导致雄激素暴露减少，从而在胎儿期导致隐睾症和/或成年期精子产生减少。
