Human loss-of-function mutations in SEC23B result in congenital dyserythropoietic anemia type II (CDAII). Complete deficiency of Sec23b in mice leads to perinatal death caused by massive degeneration of professional secretory tissues. Functions of SEC23B in postnatal mice are unclear. In this study, we generated knockout (Ko) mice with deletion of exons 5 and 6 of Sec23b and knockin (Ki) mice with the E109K mutation, the most common CDAII missense mutation. Despite decreased SEC23B protein level, Sec23bki/ki mice showed no obvious abnormalities. Hemizygous (Sec23bki/ko) mice exhibit a partial lethal phenotype, with only half of expected mice survive past weaning. Sec23bki/ko pancreas had exocrine insufficiency and chronic pancreatitis histology, as well as increased ER stress and apoptosis. Moreover, Sec23bki/ko mice exhibited severe growth restriction accompanied by growth hormone (GH) insensitivity, reminiscent of the Laron syndrome. Growth restriction is not associated with hepatocyte-specific Sec23b deletion, suggesting non-liver origin of the phenotype. Inflammation associated with chronic pancreatic deficiency may explain GH insensitivity in Sec23bki/ko mice. Our results indicate that phenotype severities are linked to the residual functions of SEC23B, demonstrating the importance of SEC23B in pancreatic acinar function in adult mice. The Sec23bki/ko mice provide a novel model of chronic pancreatitis and growth retardation.
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