Confirmation of the role of N-acetyltransferase 2 in teratogen-induced cleft palate using transgenics and knockouts.
Previous work on Dilantin- and hydrocortisone-induced cleft palate and cleft lip with or without cleft palate using congenics for the N-acetyltransferase loci (Nat1 and Nat2 are closely linked) and recombinant inbred lines implicated the Nat1,2 region in susceptibility to teratogen-induced orofacial clefting. Since Nat1 does not differ between the two strains, Nat2 appeared to be responsible. We have now tested this conclusion using transgenics and knockouts. Transgenics for human NAT1 (equivalent to mouse Nat2) and knockouts for Nat2 were tested for susceptibility to Dilantin, hydrocortisone, and 6-aminonicotinamide-induced orofacial clefting. We found that Nat2 greatly influences teratogen-induced orofacial clefting on the A/J background but not on the C57BL/6J background. The magnitude and direction of the effects depended on which teratogen was used. The Nat2 knockout did not make C57BL/6J susceptible or A/J (already with very low activity) more susceptible but significantly decreased sporadic clefting in the A/J strain. We conclude that only the A/J strain, with several loci affecting orofacial clefting, is influenced by Nat2.
Erickson
Robert P
RP
Department of Pediatrics, University of Arizona, Tucson, Arizona 85724-5073, USA. erickson@peds.arizona.edu
Cao
Wen
W
Acuña
Diana K
DK
Strnatka
Diana W
DW
Hunter
Robert J
RJ
Chau
Binh T
BT
Wakefield
Larissa V
LV
Sim
Edith
E
McQueen
Charlene A
CA
D015120:6-Aminonicotinamide / Q000633:toxicity; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002971:Cleft Lip / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D002972:Cleft Palate / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000633:toxicity; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010672:Phenytoin / Q000633:toxicity; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013723:Teratogens / Q000633:toxicity
D017931:DNA Primers; D007527:Isoenzymes; D012333:RNA, Messenger; D013723:Teratogens; D015120:6-Aminonicotinamide; D010672:Phenytoin; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C524206:Nat2 enzyme, mouse; D006854:Hydrocortisone