A Ufd2/D4Cole1e chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (Wld(S)) mouse

Exons of three genes were identified within the 85-kilobase tandem triplica tion unit of the slow Wallerian degeneration mutant mouse, C57BL/Wld(S). Ub iquitin fusion degradation protein 2 (Ufd2) and a previously undescribed ge ne, D4Cole1e, span the proximal and distal boundaries of the repeat unit, r espectively. They have the same chromosomal orientation and form a chimeric gene when brought together at the boundaries between adjacent repeat units in Wld(S). The chimeric mRNA is abundantly expressed in the nervous system and encodes an in-frame fusion protein consisting of the N-terminal 70 ami no acids of Ufd2, the C-terminal 302 amino acids of D4Cole1e, and an aspart ic acid formed at the junction. Antisera raised against synthetic: peptides detect the expected 43-kDa protein specifically in Wld(S) brain. This expr ession pattern, together with the previously established role of ubiquitina tion in axon degeneration, makes the chimeric gene a promising candidate fo r Wld. The third gene altered by the triplication. Rbp7, is a novel member of the cellular retinoid-binding protein family and is highly expressed in white adipose tissue and mammary gland. The whole gene lies within the repe at unit leading to overexpression of the normal transcript in Wld(S) mice. However, it is undetectable on Northern blots of Wld(S) brain and seems unl ikely to be the Wld gene. These data reveal both a candidate gene for Wld a nd the potential of the Wld(S) mutant for studies of ubiquitin and retinoid metabolism.