THE SAME GENOMIC REGION IS DISRUPTED IN 2 TRANSGENE-INDUCED LIMB DEFORMITY ALLELES

Mutations of the mouse limb deformity locus, ld, map to Chromosome (Chr) 2 and result in defects in the morphogenesis and patterning of the limb and kidney. Complementation studies have defined the existence of five recessive ld alleles. Remarkably, two of these, ld(TgHd) and ld(TgBri), are transgene-induced mutations. Recovery of the first transgene insertional allele, ld(TgHd) facilitated the molecular cloning of a large (> 200 kb) candidate gene at the ld locus. This gene is broadly transcribed and encodes a set of novel protein isoforms, termed formins. Here we present characterization of the ld(TgBri) mutation that supports the molecular identification of the ld gene. We show that the ld(TgBri) fails to complement both the ld(TgHd) and the ld(OR) alleles and that it has undergone a genomic deletion that disrupts the cloned ld gene and its transcripts. Curiously, the ld(TgBri) deletion encompasses the same 11-kb interval in which the ld(TgHd) insertion occurred and in which a chromosomal rearrangement has been identified in a third allele, ld(In2). These findings suggest that this region of the ld gene is a preferential site for illegitimate recombination.