TY - JOUR
T1 - 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
AU - Ji, Yonggang
AU - Walkowicz, Mitchell J.
AU - Buiting, Karin
AU - Johnson, Dabney K.
AU - Tarvin, Rocio E.
AU - Rinchik, Eugene M.
AU - Horsthemke, Bernhard
AU - Stubbs, Lisa
AU - Nicholls, Robert D.
N1 - Funding Information:
This paper is dedicated to Drs Liane and William Russell for their insight in the generation of radiation-induced developmental mutants. We thank James M. Amos-Landgraf and Nancy A. Rebert for technical assistance and Drs E.E. Eichler, P.A. Hunt and H.F. Willard for critical reading of the manuscript. This work was supported by Clinical Research grants from the March of Dimes Birth Defects Foundation (R.D.N.), the Pew Scholars Program in the Biomedical Sciences (R.D.N.), the Department of Energy under contracts nos DE-AC05-960R22464 (E.M.R., D.K.J. and L.J.S.) and W-7405-ENG-48 (L.J.S.), the National Center for Human Genome Research grant HG00370 (E.M.R.) and by an NIH minority fellowship from the Skin Diseases Research Center at University Hospitals of Cleveland (R.E.T.).
PY - 1999
Y1 - 1999
N2 - 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 chromosome 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.
AB - 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 chromosome 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.
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U2 - 10.1093/hmg/8.3.533
DO - 10.1093/hmg/8.3.533
M3 - Article
C2 - 9949213
AN - SCOPUS:0033016617
SN - 0964-6906
VL - 8
SP - 533
EP - 542
JO - Human molecular genetics
JF - Human molecular genetics
IS - 3
ER -