Originally published as Genetics Published Articles Ahead of Print on March 21, 2005.

Genetics, Vol. 170, 345-353, May 2005, Copyright © 2005
doi:10.1534/genetics.104.038620

A Gene(s) for All-trans-Retinoic Acid-Induced Forelimb Defects Mapped and Confirmed to Murine Chromosome 11

Grace S. Lee*, Rita M. Cantor{dagger}, Arin Abnoosian*, Euisun Park*, Mitsuko L. Yamamoto*, David N. Hovland, Jr.{ddagger} and Michael D. Collins*,1

* Molecular Toxicology Interdepartmental Program, UCLA School of Public Health, Los Angeles, California 90095
{dagger} Department of Human Genetics and Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
{ddagger} Amgen, Thousand Oaks, California 91320

1 Corresponding author: UCLA School of Public Health, CHS 71-297, 10833 Le Conte Ave., Los Angeles, CA 90095.
E-mail: mdc{at}ucla.edu

All-trans-retinoic acid (RA) induces various anatomical limb dysmorphologies in mice dependent on the time of exposure. During early limb development, RA induces forelimb ectrodactyly (digital absence) with varying susceptibilities for different inbred mouse strains; C57BL/6N are highly susceptible while SWV are resistant. To isolate the genetic basis of this defect, a full-genome scan was performed in 406 backcross fetuses of F1 males to C57BL/6N females. Fetuses were exposed via a maternal injection of 75 mg of RA per kilogram of body weight on gestational day 9.25. The genome-wide analysis revealed significant linkage to a chromosome 11 locus near D11Mit39 with a maximum LOD score of 9.0 and to a chromosome 4 locus near D4Mit170. An epistatic interaction was detected between loci on chromosome 11 (D11Mit39) and chromosome 18 (D18Mit64). Linkage to the chromosome 11 locus (D11Mit39) was confirmed in RA-treated backcross fetuses of F1 females to C57BL/6N males. Loci associated with bone density/mass in both human and mouse were previously detected in the same region, suggesting a mechanistic linkage with bone homeostasis. The human syntenic region of this locus has been previously linked to Meckel syndrome; the phenotype includes postaxial polydactyly, an ectopic digital defect hypothesized to be induced by a common molecular pathway with ectrodactyly.