Genome-wide identification of mouse congenital heart disease loci.
Empirical evidence supporting a genetic basis for the etiology of congenital heart disease (CHD) is limited and few disease-causing mutations have been identified. To identify novel CHD genes, we performed a forward genetic screen to identify mutant mouse lines with heritable CHD. Lines with recessive N-ethyl-N-nitrsourea-induced CHD-causing mutations were identified using a three-generation backcross. A hierarchical screening protocol was used to test the hypothesis that the fetal-to-neonatal circulatory transition unmasks the specific structural heart defects observed in CHD. Mice with heart defects were efficiently ascertained by selecting for pups exhibiting perinatal lethality and characterizing their cardiac pathology. A marked increase of perinatal lethality was observed in the mutagen-treated cohort compared with an untreated backcross population. Cardiac pathology on perinatal lethals revealed cardiovascular defects in 79 pups from 47 of 321 mutagenized lines. All identified structural abnormalities were analogous to previously described forms of human CHD. Furthermore, the phenotypic recurrence and variance patterns across all lines were similar to human CHD prevalence and recurrence patterns. We mapped the locus responsible for heritable atrioventricular septal defects in six lines (avc1-6). Our screen demonstrated that 'sporadic' CHD may have major genetic component and established a practical, efficient approach for identifying CHD candidate genes.
Kamp
Anna
A
Department of Pediatrics, The University of Chicago, Chicago, IL 60637, USA.
Peterson
Michael A
MA
Svenson
Karen L
KL
Bjork
Bryan C
BC
Hentges
Kathryn E
KE
Rajapaksha
Tharinda W
TW
Moran
Jennifer
J
Justice
Monica J
MJ
Seidman
Jon G
JG
Seidman
Christine E
CE
Moskowitz
Ivan P
IP
Beier
David R
DR
D000818:Animals; D000831:Animals, Newborn; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005038:Ethylnitrosourea; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods*; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
D005038:Ethylnitrosourea