Genetic localization and transmission of the mouse osteopetrotic grey-lethal mutation

The grey-lethal (gl) mouse is the most relevant animal model for recessive osteopetrosis, a genetic defect affecting bone resorption. To localize the gl gene, two novel backcrosses between the gl mutant strain GL/Le dl(J) +/ gl and with the Mus spretus or the Mus m. molossinus have been generated a nd typed with 19 DNA markers representative of genes or microsatellites. In the Mus m. molossinus backcross, the gl locus cosegregates with the D10Mit 108,109,184,193,254,255 markers within a 1 centimorgan genetic interval bet ween the markers (D10Mit54,55,215,Cd24a) and D10Mit148. Our results have al so eliminated all the five candidate genes previously localized to this reg ion (Braf-rs1, Fyn, Cd24a, Ros1, and Gja1). On the Mus spretus background, segregation distortion due to a similar to threefold differential survival resulted in a severe deficit in gl/gl animals, indicating the presence of m odifier genes. We have also characterized nine cosegregating microsatellite markers closely linked to gl as defined by their specific polymorphisms fo r the Chromosome (Chr) 10 harboring the gl mutation. Screening of several m ouse inbred strains for these polymorphic markers revealed an identical pat tern between gl and 129/SvEms, suggesting that the gl mutation arose on thi s genetic background. The linkage between this polymorphic region and the g l locus provides an entry point to produce a physical map to isolate the gl gene.