Luca De Toni1, Andrea Di Nisio1, Elena Speltra1, Maria Santa Rocca1, Marco Ghezzi1, Daniela Zuccarello1, Nunzio Turiaco1, Alberto Ferlin1, Carlo Foresta1. 1. 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.
Abstract
CONTEXT: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
CONTEXT: 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. OBJECTIVE: To study the possible association between rs2274911 polymorphism and male fertility and/or cryptorchidism. Design, Patients, Settings: A total of 611 subjects, including 343 infertilepatients, 197 normozoospermic controls, and 71 cryptorchid newborns, were retrospectively selected. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Bárbara Matos; Daniela Patrício; Magda C Henriques; Maria J Freitas; Rui Vitorino; Iola F Duarte; John Howl; Paula A Oliveira; Fernanda Seixas; José A Duarte; Rita Ferreira; Margarida Fardilha Journal: Cell Oncol (Dordr) Date: 2020-10-19 Impact factor: 6.730
Authors: Luca De Toni; Andrea Garolla; Massimo Menegazzo; Sabina Magagna; Andrea Di Nisio; Iva Šabović; Maria Santa Rocca; Valentina Scattolini; Andrea Filippi; Carlo Foresta Journal: PLoS One Date: 2016-12-16 Impact factor: 3.240