Ra. Akhtar et Ag. Smith, Chromosomal linkage analysis of porphyria in mice induced by hexachlorobenzene-iron synergism: a model of sporadic porphyria cutanea tarda, PHARMACOGEN, 8(6), 1998, pp. 485-494
Genetic susceptibility to toxic chemicals is of major importance but most s
tudies concentrate on candidate genes and searches for unknown susceptibili
ty genes are uncommon. Human sporadic porphyria cutanea tarda is usually pr
ecipitated by alcohol, oestrogens, hepatitis viruses, HIV or haemodialysis.
The mechanism is not known but there is a role for iron metabolism and an
underlying genetic predisposition is suspected. A similar porphyria in huma
ns has also been caused by hexachlorobenzene, These human porphyrias can be
modelled in iron-loaded mice exposed to hexachlorobenzene, in which C57BL/
10ScSn is a prototype susceptible strain whereas DBA/2 mice are extremely r
esistant. A search for susceptibility genes was undertaken using complex tr
ait analysis with DNA microsatellite markers of 'high' and 'low' responders
from an F-2 intercross. Correlation of markers with susceptibility defined
as accumulation of uroporphyrin in the liver, was assessed by chi-sqnared
test for the proportion of C57BL/10ScSn and DBA/2 alleles present. Suscepti
bility loci on chromosomes 12, 14 and 17 were identified, Further analysis
of markers on chromosomes 14 and 17 by MAPMAKER/EXP and MAPMAKER/QTL gave L
OD scores of 7.3 and 3.6, respectively. Typing of chromosome 12 for the Ahr
gene, using a restriction fragment length polymorphism distinguishing betw
een the b-1 and d alleles, gave significant but not perfect linkage, Howeve
r no strong association between alleles or expression of Cyp1a1/2 genes, re
gulated by Ahr, and susceptibility for porphyria was detected. The results
demonstrate that the porphyria induced by hexachlorobenzene in C57BL/10ScSn
mice is a complex trait determined by at least three genes, which may be o
f relevance to susceptibility in the development of sporadic porphyria cuta
nea tarda and unknown aspects of liver damage. Pharmacogenetics 8:485-494.
(C) 1998 Lippincott Williams & Wilkins.