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Polymorphism rs2274911 of GPRC6A as a Novel Risk Factor for Testis Failure

Luca De Toni1, Andrea Di Nisio1, Elena Speltra1

  • 1Department 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.

The Journal of Clinical Endocrinology and Metabolism
|January 7, 2016
PubMed
Abstract

Insights

The G protein-coupled receptor GPRC6A gene variant rs2274911 is linked to male infertility and cryptorchidism. GPRC6A inactivation may reduce androgen exposure, impacting fetal development and sperm production.

Area of Science:

  • Endocrinology
  • Genetics
  • Reproductive Medicine

Background:

  • The G protein-coupled receptor GPRC6A plays a role in endocrine functions, including testosterone production.
  • Inactivating GPRC6A mutations are linked to testicular failure and impaired spermatogenesis.
  • A GPRC6A polymorphism (rs2274911) is associated with prostate cancer risk.

Purpose of the Study:

  • To investigate the association between the GPRC6A rs2274911 polymorphism and male fertility or cryptorchidism.
  • To analyze the impact of GPRC6A genetic variations on reproductive health outcomes.

Main Methods:

  • Genotyping for rs2274911 polymorphism and F464Y mutation in 611 subjects (infertile patients, controls, cryptorchid newborns).
  • Measurement of serum FSH, LH, and testosterone levels.
  • In vitro functional studies of GPRC6A variants.

Main Results:

  • Homozygosity for the rs2274911 risk allele (A) increased the risk of oligozoospermia (4.60-fold) and cryptorchidism (3.52-fold).
  • Increased LH levels were observed in men with azoospermia/cryptozoospermia carrying GA and AA genotypes.
  • The F464Y mutation was found in 1.41% of cryptorchid infants. Functional studies indicated reduced receptor cell membrane exposure and ERK1/2 phosphorylation for A allele and F464Y.

Conclusions:

  • GPRC6A inactivation or reduced function is associated with decreased androgen exposure.
  • This may lead to cryptorchidism during fetal development and/or reduced sperm production in adulthood.
  • The rs2274911 polymorphism and F464Y mutation are potential contributors to male reproductive issues.

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