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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 &gt; A and c.522C &gt; T) and four in  RHOXF2/2B  (-73C &gt; G, c.202G &gt; A, c.411C &gt; T and c.679G &gt; A), of which only one (c.202G &gt; A) was found in a control group of men with normal sperm concentration. Functional analysis demonstrated that c.202G &gt; A and c.679G &gt; 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.

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