Characterization of the aryl hydrocarbon receptor repressor gene and association of its Pro185Ala polymorphism with micropenis.
BACKGROUND
Genetic background of a fetus contributes to the abnormal development after teratogen exposure. In rodents, in utero exposure to dioxins affects male external genital development. The effects of dioxins are mediated via the aryl hydrocarbon receptor (AHR) and its binding protein, aryl hydrocarbon receptor nuclear translocator (ARNT). In mice, aryl hydrocarbon receptor repressor (AHRR), which binds to ARNT in competition with AHR, plays a critical negative regulatory role in AHR signaling. We attempt to characterize the human AHRR gene and investigate the relationship between AHRR polymorphisms and the incidence of micropenis, a phenotype of undermasculinization.


METHODS
We identified and characterized the human homolog of mouse AHRR, taking advantage of the publicly available draft version of the human genome sequence. After detecting an AHRR protein polymorphism by the direct sequencing of pooled human genomic DNA, we evaluated the association between the polymorphism and the presence or absence of micropenis (< -2.5 SD) in patients with micropenis and control subjects.


RESULTS
The deduced sequence for human AHRR (715 residues) and the mouse AHRR protein exhibited 81% sequence homology to each other. The Pro185Ala polymorphism was identified between the PAS-A region and the highly conserved arginine/cysteine-rich RCFRCRL/VRC region. Forty-six percent (27/59) of patients with micropenis and 27% (22/80) of the controls were homozygous for 185Pro; this difference in frequencies was significant (P = 0.03).


CONCLUSIONS
Homozygosity for the 185Pro allele of AHRR may increase the susceptibility of a fetus to the undermasculinizing effects of dioxin exposure in utero, presumably through the diminished inhibition of AHR-mediated signaling.
Fujita
Hideki
H
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Kosaki
Rika
R
Yoshihashi
Hiroshi
H
Ogata
Tsutomu
T
Tomita
Masaru
M
Hasegawa
Tomonobu
T
Takahashi
Takao
T
Matsuo
Nobutake
N
Kosaki
Kenjiro
K
D000409:Alanine; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D006801:Humans; D008297:Male; D051379:Mice; D010413:Penis / Q000002:abnormalities*; D011110:Polymorphism, Genetic; D011392:Proline; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology
D000409:Alanine; D051792:Basic Helix-Loop-Helix Proteins; D011392:Proline; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; C492162:AHRR protein, human; C117300:Ahrr protein, mouse