学位论文详细信息
The Function of Mammalian COPII Components Sec23a and Sec23b.
COPII;Congenital Dyserythropoietic Anemia Type II;Sec23a;Sec23b;Genetics;Health Sciences;Human Genetics
Vasievich, Matthew PaulMoran, John V. ;
University of Michigan
关键词: COPII;    Congenital Dyserythropoietic Anemia Type II;    Sec23a;    Sec23b;    Genetics;    Health Sciences;    Human Genetics;   
Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/97814/mpv_1.pdf?sequence=1&isAllowed=y
瑞士|英语
来源: The Illinois Digital Environment for Access to Learning and Scholarship
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【 摘 要 】

In all eukaryotic cells, cargo proteins are transported from the endoplasmic reticulum (ER) to the Golgi apparatus in COPII-coated vesicles. Human diseases have recently been described that result from inherited mutations in the paralagous genes SEC23A and SEC23B, which encode a key component of the COPII vesicle coat. In this thesis, I explore the phenotypes of gene targeted mice deficient for the mouse SEC23 orthologs Sec23a and Sec23b.Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessivedisorder characterized by mild to severe anemia, and recently reported to be due to mutations in the SEC23B gene. Mice homozygous for a gene trap insertion in the last intron of the mouse Sec23b gene (Sec23b gt/gt) were demonstrated to exhibit massive pancreatic degeneration and die within a day of birth, with no evidence of anemia on blood analysis. Chimeric mice generated by transplantation of Sec23b gt/gt hematopoietic precursor cells into wild type mice demonstrated full reconstitution of erythropoiesis, as well as other blood cell lineages. Mass spectrometry analysis of Sec23b gt/gt RBC ghosts prepared from chimeric mice using a comparative SILAC approach detected no proteins that were quantitatively decreased compared to control RBC ghosts. These results suggest divergence in tissue-specific SEC23B function between mice and humans.Humans with mutations in SEC23A are affected with Cranio-Lenticulo-Sutural Dysplasia (CLSD), which is characterized by late closure of the cranial fontanelles and mild mental retardation. Mice with a gene trap insertion in the second intron of the Sec23a gene die between day 10.5 and 11.5 of embryogenesis. Mice heterozygous for both the Sec23a gt and Sec23b gt alleles (Sec23a+/gt Sec23b+/gt) are viable and fertile with no apparent pathologic phenotype. However, Sec23a gt/gt Sec23b+/gt mice die at an earlier time point in embryogenesis than Sec23a gt/gt mice, suggesting functional overlap between SEC23A and SEC23B. These studies have shown that humans and mice with mutations in Sec23a and Sec23b have disparate but tissue specific phenotypes. Thisdemonstrates the importance of the COPII pathway in human disease and could suggest functional divergence of these isoforms over evolutionary time between human and mouse.

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