• PMID: 18562473
• Gene Name: RBMXL2
• Condition: Male infertility
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Male infertility

Haploinsufficiency of the germ cell-specific nuclear RNA binding protein hnRNP G-T prevents functional spermatogenesis in the mouse

Ehrmann I, Dalgliesh C, Tsaousi A, Paronetto MP, Heinrich B, Kist R, Cairns P, Li W, Mueller C, Jackson M, Peters H, Nayernia K, Saunders P, Mitchell M, Stamm S, Sette C, Elliott DJ.

Human HNRNPGT, encoding the protein hnRNP G-T, is one of several autosomal retrogenes derived from RBMX. It has been suggested that HNRNPGT functionally replaces the sex-linked RBMX and RBMY genes during male meiosis. We show here that during normal mouse germ cell development, hnRNP G-T protein is strongly expressed during and after meiosis when proteins expressed from Rbmx or Rbmx-like genes are absent. Amongst these Rbmx-like genes, DNA sequence analyses indicate that two other mouse autosomal Rbmx-derived retrogenes have evolved recently in rodents and one already shows signs of degenerating into a non-expressed pseudogene. In contrast, orthologues of Hnrnpgt are present in all four major groups of placental mammals. The sequence of Hnrnpgt is under considerable positive selection suggesting it performs an important germ cell function in eutherians. To test this, we inactivated Hnrnpgt in ES cells and studied its function during spermatogenesis in chimaeric mice. Although germ cells heterozygous for this targeted allele could produce sperm, they did not contribute to the next generation. Chimaeric mice with a high level of mutant germ cells were infertile with low sperm counts and a high frequency of degenerate seminiferous tubules and abnormal sperm. Chimaeras made from a 1:1 mix of targeted and wild-type ES cell clones transmitted wild-type germ cells only. Our data show that haploinsufficiency of Hnrnpgt results in abnormal sperm production in the mouse. Genetic defects resulting in reduced levels of HNRNPGT could, therefore, be a cause of male infertility in humans. FAU - Ehrmann, Ingrid AU - Ehrmann I AD - Institute of Human Genetics, Newcastle University, Central Parkway, Newcastle NE1 3BZ, UK. FAU - Dalgliesh, Caroline AU - Dalgliesh C FAU - Tsaousi, Aikaterini AU - Tsaousi A FAU - Paronetto, Maria Paola AU - Paronetto MP FAU - Heinrich, Bettina AU - Heinrich B FAU - Kist, Ralf AU - Kist R FAU - Cairns, Paul AU - Cairns P FAU - Li, Weiping AU - Li W FAU - Mueller, Christian AU - Mueller C FAU - Jackson, Michael AU - Jackson M FAU - Peters, Heiko AU - Peters H FAU - Nayernia, Karim AU - Nayernia K FAU - Saunders, Philippa AU - Saunders P FAU - Mitchell, Michael AU - Mitchell M FAU - Stamm, Stefan AU - Stamm S FAU - Sette, Claudio AU - Sette C