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 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.
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Rami
R
Khoriaty
University of Michigan Medical School, Ann Arbor, MI, USA.
Lesley
L
Everett
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Jennifer
J
Chase
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Guojing
G
Zhu
In Vivo Animal Core, Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.
Mark
M
Hoenerhoff
College of Literature Science and the Arts, University of Michigan, Ann Arbor, MI, USA.
Brooke
B
McKnight
University of Michigan Medical School, Ann Arbor, MI, USA.
Matthew P
MP
Vasievich
Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
Bin
B
Zhang
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
Kärt
K
Tomberg
Department of Physiology, University of Michigan, Ann Arbor, MI, USA.
John
J
Williams
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.|Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Ivan
I
Maillard
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.|Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.|Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.|Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.|Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
David
D
Ginsburg
D061354:Acinar Cells / Q000378:metabolism; D000375:Aging / Q000473:pathology; D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D003433:Crosses, Genetic; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D041905:Erythroid Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005854:Germ Cells / Q000378:metabolism*; D006410:Hematopoiesis; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology*; D066087:Perinatal Death; D010641:Phenotype; D019076:Transgenes; D033921:Vesicular Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
C575519:SEC23B protein, mouse; D033921:Vesicular Transport Proteins; C045073:Cre recombinase; D019426:Integrases