• PMID: 28171660
• Gene Name: RHOXF1
• Condition: Oligozoospermia, Male infertility
• Association: Associated
• Mutation: RHOXF1 (c.515G?>?A and c.522C?>?T) and four in RHOXF2/2B (-73C?>?G, c.202G?>?A, c.411C?>?T and c.679G?>?A)
• Population size: 250
• Population details: 250 patients with severe oligozoospermia
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Oligozoospermia, Male infertility

The human RHOX gene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann J, Tüttelmann F, Dworniczak B, Röpke A, Song HW, Kliesch S, Wilkinson MF, Laurentino S, Gromoll J.

The X-linked reproductive homeobox (RHOX) gene cluster encodes transcription factors preferentially expressed in reproductive tissues. This gene cluster has important roles in male fertility based on phenotypic defects of Rhox-mutant mice and the finding that aberrant RHOX promoter methylation is strongly associated with abnormal human sperm parameters. However, little is known about the molecular mechanism of RHOX function in humans. Using gene expression profiling, we identified genes regulated by members of the human RHOX gene cluster. Some genes were uniquely regulated by RHOXF1 or RHOXF2/2B, while others were regulated by both of these transcription factors. Several of these regulated genes encode proteins involved in processes relevant to spermatogenesis; e.g. stress protection and cell survival. One of the target genes of RHOXF2/2B is RHOXF1, suggesting cross-regulation to enhance transcriptional responses. The potential role of RHOX in human infertility was addressed by sequencing all RHOX exons in a group of 250 patients with severe oligozoospermia. This revealed two mutations in RHOXF1 (c.515G > A and c.522C > T) and four in RHOXF2/2B (-73C > G, c.202G > A, c.411C > T and c.679G > A), of which only one (c.202G > A) was found in a control group of men with normal sperm concentration. Functional analysis demonstrated that c.202G > A and c.679G > A significantly impaired the ability of RHOXF2/2B to regulate downstream genes. Molecular modelling suggested that these mutations alter RHOXF2/F2B protein conformation. By combining clinical data with in vitro functional analysis, we demonstrate how the X-linked RHOX gene cluster may function in normal human spermatogenesis and we provide evidence that it is impaired in human male fertility. FAU - Borgmann, Jennifer AU - Borgmann J AD - Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany. FAU - Tüttelmann, Frank AU - Tüttelmann F AD - Institute of Human Genetics, Münster, Germany. FAU - Dworniczak, Bernd AU - Dworniczak B AD - Institute of Human Genetics, Münster, Germany. FAU - Röpke, Albrecht AU - Röpke A AD - Institute of Human Genetics, Münster, Germany. FAU - Song, Hye-Won AU - Song HW AD - Department of Reproductive Medicine, University of California San Diego, La Jolla, USA. FAU - Kliesch, Sabine AU - Kliesch S AD - Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany. FAU - Wilkinson, Miles F AU - Wilkinson MF AD - Department of Reproductive Medicine, University of California San Diego, La Jolla, USA. AD - Department of Genomic Medicine, University of California San Diego, La Jolla, USA. FAU - Laurentino, Sandra AU - Laurentino S AD - Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.