TY - JOUR
T1 - Sequencing and haplotype analysis of the Activator of CREM in the Testis (ACT) gene in populations of fertile and infertile males
AU - Christensen, Greg L.
AU - Wooding, Stephen P.
AU - Ivanov, Ivaylo P.
AU - Atkins, John F.
AU - Carrell, Douglas T.
N1 - Funding Information:
Control samples obtained from the Utah Genetic Reference Project (UGRP) were collected with support from a Public Health Services research grant to the Huntsman General Clinical Research Center, number M01-RR00064, from the National Center for Research Resources. The UGRP was also supported by generous gifts from the W.M. Keck and Delores Dore Eccles Foundations. We extend our sincere thanks to all family members who participated in the UGRP.
PY - 2006/4
Y1 - 2006/4
N2 - 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.
AB - 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.
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U2 - 10.1093/molehr/gal006
DO - 10.1093/molehr/gal006
M3 - Article
C2 - 16687568
AN - SCOPUS:33646878815
SN - 1360-9947
VL - 12
SP - 257
EP - 262
JO - Molecular Human Reproduction
JF - Molecular Human Reproduction
IS - 4
ER -