Multifactorial genetics of exencephaly in SELH/Bc mice

Background: The SELH/Bc mouse strain has 10-30% exencephaly and is an anima l model for human neural tube closure defects. This study examined the numb er of causative genes, their dominance relationships, and linkage map posit ions. Methods: The SELH/Bc strain (S) was crossed to the normal LM/Bc strain (L) and frequencies of exencephaly were observed in the F-1, BC1, and F-2 gener ations. 102 F-2 males were individually testcrossed by SELH/Bc. The extreme s, the 10 highest and 10 zero exencephaly-producing F-2 sires, were typed f or 109 SSLP marker loci in a genome screen. Next, the resultant five provis ional chromosomal regions were tested for linkage in 31 F-2 exencephalic em bryos. Finally, 12 males, SS or LL for the Chr 13 region on an LM/Bc backgr ound, were testcrossed by SELH/Bc. Results: The exencephaly frequencies in the F-1 (0.3%), BC1 (4.4%), and F-2 (3.7%), and the distribution of F-2 males' testcross values (0-15.5%), ind icated that the high risk of exencephaly in SELH/Bc is due to the cumulativ e effect of two or three loci. Linkage studies indicated the location of se midominant 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. Conclusions: The high risk of exencephaly in SELH/Bc mice is caused by the cumulative effect of two to three semidominant genes. Candidate genes inclu de Msx2, Madh5, Ptch, and Irx1 (Chr 13) and Actb and Rac1 (Chr 5). (C) 2001 Wiley-Liss, Inc.