Journal Article

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

Yonggang Ji, Mitchell J. Walkowicz, Karin Buiting, Dabney K. Johnson, Rocio E. Tarvin, Eugene M. Rinchik, Bernhard Horsthemke, Lisa Stubbs and Robert D. Nicholls

in Human Molecular Genetics

Volume 8, issue 3, pages 533-542
Published in print March 1999 | ISSN: 0964-6906
Published online March 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.3.533
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

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Transcribed, low-copy repeat elements are associated with the breakpoint regions of common deletions in Prader-Willi and Angelman syndromes. We report here the identification of the ancestral gene (HERC2) and a family of duplicated, truncated copies that comprise these low-copy repeats. This gene encodes a highly conserved giant protein, HERC2, that is distantly related to p532 (HERC1), a guanine nucleotide exchange factor (GEF) implicated in vesicular trafficking. The mouse genome contains a single Herc2 locus, located in the jdf2 (juvenile development and fertility-2) interval of chromsome 7C. We have identified single nucleotide splice junction mutations in Herc2 in three independent N-ethyl-N-nitrosourea-induced jdf2 mutant alleles, each leading to exon skipping with premature termination of translation and/or deletion of conserved amino acids. Therefore, mutations in Herc2 lead to the neuromuscular secretory vesicle and sperm acrosome defects, other developmental 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.

Journal Article.  7789 words.  Illustrated.

Subjects: Genetics and Genomics

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