The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities

Transcribed, low-copy repeat elements are associated with the breakpoint re gions of common deletions in Prader-Willi and Angelman syndromes. We report here the identification of the ancestral gene (HERC2) and a family of dupl icated, truncated copies that comprise these low-copy repeats, This gene en codes a highly conserved giant protein, HERC2, that is distantly related to p532 (HERC1), a guanine nucleotide exchange factor (GEF) implicated in ves icular trafficking, The mouse genome contains a single Herc2 locus, located in the jdf2 (juvenile development and fertility-2) interval of chromosome 7C, We have identified single nucleotide splice junction mutations in Herc2 in three independent Nethyl-N-nitvosourea-induced jdf2 mutant alleles, eac h leading to exon skipping with premature termination of translation and/or deletion of conserved amino acids. Therefore, mutations in Herc2 lead to t he neuromuscular secretory vesicle and sperm acrosome defects, other develo pmental abnormalities and juvenile lethality of jdf2 mice. Combined, these findings suggest that HERC2 is an important gene encoding a GEF involved in protein trafficking and degradation pathways in the cell.