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Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice

In humans, loss of function mutations in SEC23B result in Congenital Dyserythropoietic Anemia type II (CDAII), a disease limited to defective erythroid development. Patients with two nonsense SEC23B mutations have not been reported, suggesting that complete SEC23B deficiency might be lethal. We prev...

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Autores principales: Khoriaty, Rami, Everett, Lesley, Chase, Jennifer, Zhu, Guojing, Hoenerhoff, Mark, McKnight, Brooke, Vasievich, Matthew P., Zhang, Bin, Tomberg, Kärt, Williams, John, Maillard, Ivan, Ginsburg, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906273/
https://www.ncbi.nlm.nih.gov/pubmed/27297878
http://dx.doi.org/10.1038/srep27802
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author Khoriaty, Rami
Everett, Lesley
Chase, Jennifer
Zhu, Guojing
Hoenerhoff, Mark
McKnight, Brooke
Vasievich, Matthew P.
Zhang, Bin
Tomberg, Kärt
Williams, John
Maillard, Ivan
Ginsburg, David
author_facet Khoriaty, Rami
Everett, Lesley
Chase, Jennifer
Zhu, Guojing
Hoenerhoff, Mark
McKnight, Brooke
Vasievich, Matthew P.
Zhang, Bin
Tomberg, Kärt
Williams, John
Maillard, Ivan
Ginsburg, David
author_sort Khoriaty, Rami
collection PubMed
description In humans, loss of function mutations in SEC23B result in Congenital Dyserythropoietic Anemia type II (CDAII), a disease limited to defective erythroid development. Patients with two nonsense SEC23B mutations have not been reported, suggesting that complete SEC23B deficiency might be lethal. We previously reported that SEC23B-deficient mice die perinatally, exhibiting massive pancreatic degeneration and that mice with hematopoietic SEC23B deficiency do not exhibit CDAII. We now show that SEC23B deficiency restricted to the pancreas is sufficient to explain the lethality observed in mice with global SEC23B-deficiency. Immunohistochemical stains demonstrate an acinar cell defect but normal islet cells. Mammalian genomes contain two Sec23 paralogs, Sec23A and Sec23B. The encoded proteins share ~85% amino acid sequence identity. We generate mice with pancreatic SEC23A deficiency and demonstrate that these mice survive normally, exhibiting normal pancreatic weights and histology. Taken together, these data demonstrate that SEC23B but not SEC23A is essential for murine pancreatic development. We also demonstrate that two BAC transgenes spanning Sec23b rescue the lethality of mice homozygous for a Sec23b gene trap allele, excluding a passenger gene mutation as the cause of the pancreatic lethality, and indicating that the regulatory elements critical for Sec23b pancreatic function reside within the BAC transgenes.
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spelling pubmed-49062732016-06-14 Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice Khoriaty, Rami Everett, Lesley Chase, Jennifer Zhu, Guojing Hoenerhoff, Mark McKnight, Brooke Vasievich, Matthew P. Zhang, Bin Tomberg, Kärt Williams, John Maillard, Ivan Ginsburg, David Sci Rep Article In humans, loss of function mutations in SEC23B result in Congenital Dyserythropoietic Anemia type II (CDAII), a disease limited to defective erythroid development. Patients with two nonsense SEC23B mutations have not been reported, suggesting that complete SEC23B deficiency might be lethal. We previously reported that SEC23B-deficient mice die perinatally, exhibiting massive pancreatic degeneration and that mice with hematopoietic SEC23B deficiency do not exhibit CDAII. We now show that SEC23B deficiency restricted to the pancreas is sufficient to explain the lethality observed in mice with global SEC23B-deficiency. Immunohistochemical stains demonstrate an acinar cell defect but normal islet cells. Mammalian genomes contain two Sec23 paralogs, Sec23A and Sec23B. The encoded proteins share ~85% amino acid sequence identity. We generate mice with pancreatic SEC23A deficiency and demonstrate that these mice survive normally, exhibiting normal pancreatic weights and histology. Taken together, these data demonstrate that SEC23B but not SEC23A is essential for murine pancreatic development. We also demonstrate that two BAC transgenes spanning Sec23b rescue the lethality of mice homozygous for a Sec23b gene trap allele, excluding a passenger gene mutation as the cause of the pancreatic lethality, and indicating that the regulatory elements critical for Sec23b pancreatic function reside within the BAC transgenes. Nature Publishing Group 2016-06-14 /pmc/articles/PMC4906273/ /pubmed/27297878 http://dx.doi.org/10.1038/srep27802 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Khoriaty, Rami
Everett, Lesley
Chase, Jennifer
Zhu, Guojing
Hoenerhoff, Mark
McKnight, Brooke
Vasievich, Matthew P.
Zhang, Bin
Tomberg, Kärt
Williams, John
Maillard, Ivan
Ginsburg, David
Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice
title Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice
title_full Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice
title_fullStr Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice
title_full_unstemmed Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice
title_short Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice
title_sort pancreatic sec23b deficiency is sufficient to explain the perinatal lethality of germline sec23b deficiency in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906273/
https://www.ncbi.nlm.nih.gov/pubmed/27297878
http://dx.doi.org/10.1038/srep27802
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