title: Polymorphism rs2274911 of GPRC6A as a Novel Risk Factor for Testis Failure.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Luca
authors.initials: L
authors.lastname: De Toni
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Nisio
authors.affiliation: 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.
authors.forename: Elena
authors.initials: E
authors.lastname: Speltra
authors.affiliation: 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.
authors.forename: Maria Santa
authors.initials: MS
authors.lastname: Rocca
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Ghezzi
authors.affiliation: 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.
authors.forename: Daniela
authors.initials: D
authors.lastname: Zuccarello
authors.affiliation: 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.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Turiaco
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferlin
authors.affiliation: 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.
authors.forename: Carlo
authors.initials: C
authors.lastname: Foresta
mesh_terms: D002675:Child, Preschool; D003456:Cryptorchidism / Q000097:blood / Q000235:genetics; D005640:Follicle Stimulating Hormone / Q000097:blood; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007248:Infertility, Male / Q000097:blood / Q000235:genetics; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012189:Retrospective Studies; D013733:Testicular Diseases / Q000097:blood / Q000235:genetics*; D013739:Testosterone / Q000097:blood
chemical_list: C488584:GPRC6A protein, human; D043562:Receptors, G-Protein-Coupled; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone