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 breakpointregions of common deletions in Prader-Willi and Angelman syndromes. Wereport here the identification of the ancestral gene ( HERC2 ) and a familyof duplicated, truncated copies that comprise these low-copy repeats. Thisgene encodes a highly conserved giant protein, HERC2, that is distantlyrelated to p532 (HERC1), a guanine nucleotide exchange factor (GEF)implicated in vesicular trafficking. The mouse genome contains a singleHerc2 locus, located in the jdf2 (juvenile development and fertility-2)interval of chromosome 7C. We have identified single nucleotide splicejunction mutations in Herc2 in three independentN-ethyl-N-nitrosourea-induced jdf2 mutant alleles, each leading to exonskipping with premature termination of translation and/or deletion ofconserved amino acids. Therefore, mutations in Herc2 lead to theneuromuscular secretory vesicle and sperm acrosome defects, otherdevelopmental abnormalities and juvenile lethality of jdf2 mice. Combined,these findings suggest that HERC2 is an important gene encoding a GEFinvolved in protein trafficking and degradation pathways in the cell.