A very large protein with diverse functional motifs is deficient inrjs(runty, jerky, sterile) mice

Abstract

Three radiation-induced alleles of the mouseplocus,p6H,p25H, andpbs, cause defects in growth, coordination, fertility, and maternal behavior in addition topgene-related hypopigmentation. These alleles are associated with disruption of thepgene plus an adjacent gene involved in the disorders listed. We have identified this adjacent gene, previously namedrjs(runtyjerkysterile), by positional cloning. TherjscDNA is very large, covering 15,264 nucleotides. The predictedrjs-encoded protein (4,836 amino acids) contains several sequence motifs, including three RCC1 repeats, a structural motif in common with cytochromeb5, and a HECT domain in common with E6-AP ubiquitin ligase. On the basis of sequence homology and conserved synteny, therjsgene 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, a region commonly deleted in most Prader–Willi syndrome patients. Previous work has suggested that the multiple phenotypes inrjsmice might be due to a common neuroendocrine defect. In addition to this proposed mode of action, alternative functions of therjsgene are evaluated in light of its known protein homologies.