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

Ingrid Ehrmann, Caroline Dalgliesh, Aikaterini Tsaousi, Maria Paola Paronetto, Bettina Heinrich, Ralf Kist, Paul Cairns, Weiping Li, Christian Mueller, Michael Jackson, Heiko Peters, Karim Nayernia, Philippa Saunders, Michael Mitchell, Stefan Stamm, Claudio Sette, David J. Elliott

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2803-2818
Number of pages16
JournalHuman Molecular Genetics
Volume17
Issue number18
DOIs
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Haploinsufficiency of the germ cell-specific nuclear RNA binding protein hnRNP G-T prevents functional spermatogenesis in the mouse'. Together they form a unique fingerprint.

  • Cite this

    Ehrmann, I., Dalgliesh, C., Tsaousi, A., Paronetto, M. P., 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, D. J. (2008). Haploinsufficiency of the germ cell-specific nuclear RNA binding protein hnRNP G-T prevents functional spermatogenesis in the mouse. Human Molecular Genetics, 17(18), 2803-2818. https://doi.org/10.1093/hmg/ddn179