Abstract
IntroductionGenes involved in testicular differentiation, spermatogenesis, proliferation and apoptosis of germ cells have been shown to evolve rapidly and display rapid DNA changes. These genes are therefore good candidates for explaining impairments in spermatogenesis. Initial studies of some of these genes appear to confirm this hypothesis. The RHOXF2 candidate gene belongs to the RHOX family clustered in Xq24 and is specifically expressed in the testis. It contains four exons and codes for a 288 amino acid (aa) transcription factor. It has a high degree of homology (>99.9%) with its paralogue RHOXF2B, which is also preferentially expressed in the testis.ObjectivesTo sequence RHOXF2 and RHOXF2B in intracytoplasmic sperm injection (ICSI) patients and identify any single-nucleotide polymorphisms (SNPs) associated with impaired spermatogenesis.MaterialsA cohort of 327 patients in ICSI programmes at Poissy and Bichat hospitals. All patients gave their written, informed consent to participation. One hundred patients had unaffected spermatogenesis and 227 displayed impaired spermatogenesis.MethodsThe four exons in each of RHOXF2 and RHOXF2B were sequenced in 47 patients with oligospermia or non-obstructive azoospermia. Given that exons 2 and 3 were found to harbour most of the SNPs, only these two exons were sequenced in the remaining 280 subjects.ResultsDue to the extremely high degree of sequence identity between RHOXF2 and RHOXF2B, we were not able to distinguish between the sequences of these two genes. Although 9 SNPs were identified, there were no significant frequency differences between ICSI patients with normal vs. impaired spermatogenesis. Two insertions were identified: a 21-nucleotide insertion was retrieved in both groups and a guanine insertion (inducing a premature stop codon) only found in two patients with impaired spermatogenesis.Conclusion/outlookRHOXF2 is a good candidate for rapid evolution by positive selection. Analysis of the polymorphism frequency in exons 2 and 3 did not allow us to correlate the identified SNPs with male infertility. However, a single nucleotide insertion was identified only in men with impaired spermatogenesis. Further work will be needed to establish whether genetic changes in RHOXF2 can give rise to defects in spermatogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-4190-24-3) contains supplementary material, which is available to authorized users.
Highlights
Genes involved in testicular differentiation, spermatogenesis, proliferation and apoptosis of germ cells have been shown to evolve rapidly and display rapid DNA changes
RHOXF2, USP-26, Spo-11 and PRM1 and PRM2 are involved in different stages of spermatogenesis, NROB1 and REα are involved in testicular differentiation, and HYAL3 and TSARG1 are involved in the proliferation/apoptosis of germ cells
Mutations in the RHOXF2 and RHOXF2B genes might explain some cases of male infertility
Summary
Genes involved in testicular differentiation, spermatogenesis, proliferation and apoptosis of germ cells have been shown to evolve rapidly and display rapid DNA changes. The RHOXF2 candidate gene belongs to the RHOX family clustered in Xq24 and is expressed in the testis It contains four exons and codes for a 288 amino acid (aa) transcription factor. The study of genetic divergence between humans and chimpanzees [1] revealed the existence of certain groups of rapidly evolving genes subject to positive selection This translates into a relatively high frequency of nucleotide sequence changes and amino acid substitutions. Studies of human single nucleotide polymorphisms (SNPs) have shown that some human genes have evolved in response to positive selection pressure [2] This mechanism seems to preferentially affect genes involved in gametogenesis, apoptosis and immunity. We compared cases and controls in terms of the frequency of the newly identified SNPs
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