Genes, environment, and orofacial clefting: N-acetyltransferase and folic acid.
Nonsyndromic orofacial clefting has been the subject of intense studies, both genetic and epidemiological. The findings have frequently been controversial because of lack of reproducibility. Mouse models provide the potential both for genetic and environmental uniformity. We have chosen to study the role of genetic susceptibility to teratogen-induced orofacial clefting, using 2 drugs (dilantin and corticosteroid) and 1 nondrug teratogen (6-aminonicotinamide). The strongest single genetic influence we have found is N-acetyltransferase 2. Our recent work and that of others suggest that the influence of this locus is mediated through alterations in folate metabolism. Our results support epidemiological findings in humans and possibly implicate altered cytosine methylation, potentially caused by environmental factors, at least in the A/J model.
Erickson
Robert P
RP
Department of Pediatrics, University of Arizona College of Medicine, Tucson, Arizona 85724-5073, USA. erickson@peds.arizona.edu
D015120:6-Aminonicotinamide / Q000633:toxicity*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002971:Cleft Lip / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D002972:Cleft Palate / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D005492:Folic Acid / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006854:Hydrocortisone / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010672:Phenytoin / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D012307:Risk Factors
D015120:6-Aminonicotinamide; D010672:Phenytoin; D005492:Folic Acid; D001191:Arylamine N-Acetyltransferase; C524206:Nat2 enzyme, mouse; D006854:Hydrocortisone