Multifactorial genetics of exencephaly in SELH/Bc mice

The SELH/Bc mouse strain has 10-30% exencephaly and is an animal model for human neural tube closure defects. This study examined the number of causative genes, their dominance relationships, and linkage map positions.

The SELH/Bc strain (S) was crossed to the normal LM/Bc strain (L) and frequencies of exencephaly were observed in the F(1), BC(1), and F(2) generations. 102 F(2) males were individually testcrossed by SELH/Bc. The extremes, the 10 highest and 10 zero exencephaly-producing F(2) sires, were typed for 109 SSLP marker loci in a genome screen. Next, the resultant five provisional chromosomal regions were tested for linkage in 31 F(2) exencephalic embryos. Finally, 12 males, SS or LL for the Chr 13 region on an LM/Bc background, were testcrossed by SELH/Bc.

The exencephaly frequencies in the F(1) (0.3%), BC(1) (4.4%), and F(2) (3.7%), and the distribution of F(2) males' testcross values (0-15.5%), indicated that the high risk of exencephaly in SELH/Bc is due to the cumulative effect of two or three loci. Linkage studies indicated the location of semidominant exencephaly-risk genes on Chr 13 near D13Mit13 (P < 0.001), Chr 5 near D5Mit168 (P < 0.025), and possibly Chr 11 near D11Mit10 (P < 0.07). The gene on Chr 13, Exen1, and the strong role of other loci were confirmed by the congenic males.

The high risk of exencephaly in SELH/Bc mice is caused by the cumulative effect of two to three semidominant genes. Candidate genes include Msx2, Madh5, Ptch, and Irx1 (Chr 13) and Actb and Rac1 (Chr 5).