Sequencing and haplotype analysis of the Activator of CREM in the Testis (ACT) gene in populations of fertile and infertile males
1Andrology and IVF Laboratories, 2Department of Physiology, 3Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA and 4Biosciences Institute, University College, Cork, Ireland
5 To whom correspondence should be addressed at: Andrology and IVF Laboratories, University of Utah School of Medicine, 675 Arapeen Drive, Suite 205, Salt Lake City, UT 84108, USA. E-mail: dcarrell{at}med.utah.edu
cAMP-responsive element modulator (CREM) is a key transcription factor in the differentiation of round spermatids into mature spermatozoa. During spermiogenesis, CREM is regulated in part by activator of CREM in the testis (ACT), which activates CREM in a phosphorylation-independent fashion. We hypothesized that the ACT gene, which is expressed exclusively in the testis, could be involved in male factor infertility in patients with idiopathic-impaired spermatogenesis. To test this hypothesis, we sequenced the coding regions and flanking intronic regions of the ACT gene in 96 azoo- or oligospermic patients and 69 fertile controls. A total of 12 single-nucleotide polymorphisms (SNPs) was identified, and four of them leading to amino acid substitutions. An association study was performed based on calculated haplotype frequencies, and statistically significant differences were found between the patient and control populations for some haplotypes. To help establish the evolutionary relationships between the haplotypes, the coding regions of both the chimpanzee and the gorilla ACT gene were sequenced and evaluated. To test whether the different haplotypes conferred a functional change to the ACT protein, a yeast two-hybrid assay was designed to test the interaction between the two most divergent ACT haplotypes and their known binding partners, CREM and KIF17b. We identified one ACT haplotype that had a 45% reduction in its interaction with CREM. Our results suggest that different haplotypes within the ACT gene may contribute to male factor subfertility.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. T. Carrell, B. R. Emery, and S. Hammoud Altered protamine expression and diminished spermatogenesis: what is the link? Hum. Reprod. Update, May 1, 2007; 13(3): 313 - 327. [Abstract] [Full Text] [PDF]
|
|