A VERY LARGE PROTEIN WITH DIVERSE FUNCTIONAL MOTIFS IS DEFICIENT IN RJS (RUNTY, JERKY, STERILE) MICE

Three radiation-induced alleles of the mouse p locus, p(6H), p(25H), a nd p(bs), cause defects in growth, coordination, fertility, and matern al behavior in addition to p gene-related hypopigmentation. These alle les are associated with disruption of the p gene plus an adjacent gene involved hn the disorders listed. We have identified this adjacent ge ne, previously named rjs (runty jerky sterile), by positional cloning. The rjs cDNA is very large, covering 15,264 nucleotides. The predicte d rjs-encoded protein (4,836 amino acids) contains several sequence mo tifs, including three RCC1 repeats, a structural motif in common with cytochrome b(5), and a HECT domain in common with Eg-BP ubiquitin liga se, Ore the basis of sequence homolog and conserved synteny; the rjs g ene is the single mouse homolog of a previously described five- or six -member human gene family. This family is represented by at least two genes, HSC7541 and KIAA0393, from human chromosome 15q11-q13. HSC7541 and KIAA0393 lie close to, or within, st region commonly deleted in mo st Prader-Willi syndrome patients. Previous work has suggested that th e multiple phenotypes in rjs mice might be due to a common neuroendacr ine defect, In addition to this proposed mode of action, alternative f unctions of the rjs gene are evaluated in light of its known protein h omologies.