Sequencing and haplotype analysis of the Activator of CREM in the Testis (ACT) gene in populations of fertile and infertile males

Greg L. Christensen, Stephen P. Wooding, Ivaylo P. Ivanov, John F. Atkins, Douglas T. Carrell

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)257-262
Number of pages6
JournalMolecular Human Reproduction
Volume12
Issue number4
DOIs
StatePublished - Apr 2006

Fingerprint

Cyclic AMP Response Element Modulator
Haplotypes
Testis
Population
Genes
Male Infertility
Spermatogenesis
Gorilla gorilla
Two-Hybrid System Techniques
Spermatids
Pan troglodytes
Amino Acid Substitution
activator of CREM in testis (ACT)
Single Nucleotide Polymorphism
Spermatozoa
Transcription Factors
Phosphorylation

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Genetics
  • Developmental Biology
  • Embryology
  • Cell Biology

Cite this

Sequencing and haplotype analysis of the Activator of CREM in the Testis (ACT) gene in populations of fertile and infertile males. / Christensen, Greg L.; Wooding, Stephen P.; Ivanov, Ivaylo P.; Atkins, John F.; Carrell, Douglas T.

In: Molecular Human Reproduction, Vol. 12, No. 4, 04.2006, p. 257-262.

Research output: Contribution to journalArticle

Christensen, Greg L. ; Wooding, Stephen P. ; Ivanov, Ivaylo P. ; Atkins, John F. ; Carrell, Douglas T. / Sequencing and haplotype analysis of the Activator of CREM in the Testis (ACT) gene in populations of fertile and infertile males. In: Molecular Human Reproduction. 2006 ; Vol. 12, No. 4. pp. 257-262.
@article{346fa2b73d2b4ec1a3e73cae7641b866,
title = "Sequencing and haplotype analysis of the Activator of CREM in the Testis (ACT) gene in populations of fertile and infertile males",
abstract = "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.",
author = "Christensen, {Greg L.} and Wooding, {Stephen P.} and Ivanov, {Ivaylo P.} and Atkins, {John F.} and Carrell, {Douglas T.}",
year = "2006",
month = "4",
doi = "10.1093/molehr/gal006",
language = "English (US)",
volume = "12",
pages = "257--262",
journal = "Molecular Human Reproduction",
issn = "1360-9947",
publisher = "Oxford University Press",
number = "4",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=33646878815&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646878815&partnerID=8YFLogxK

U2 - 10.1093/molehr/gal006

DO - 10.1093/molehr/gal006

M3 - Article

C2 - 16687568

AN - SCOPUS:33646878815

VL - 12

SP - 257

EP - 262

JO - Molecular Human Reproduction

JF - Molecular Human Reproduction

SN - 1360-9947

IS - 4

ER -