In humans, 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 with no CDAII phenotype. Functions of SEC23B in postnatal mice are unclear. In this study, we generated mice with the E109K mutation (Sec23bki/ki), the most common CDAII missense mutation. The E109K mutation leads to decreased SEC23B protein level, and results in mislocalization of SEC23B. However, Sec23bki/ki mice showed no obvious abnormalities. Hemizygous (Sec23bki/ko) mice exhibit a partial lethal phenotype, with half of these mice survive past weaning. Sec23bki/ko mice had chronic pancreatic histology changes such as interstitial fibrosis, white blood cell infiltration and exocrine insufficiency. Increased ER stress was found in Sec23bki/ko pancreas, associated with increased apoptosis. Moreover, Sec23bki/ko mice exhibited severe growth retardation accompanied by growth hormone (GH) insensitivity, reminiscent of the Laron syndrome. Interestingly, mice with hepatocyte-specific Sec23b deletion grow normally, 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 in mice, further demonstrating a critical role of SEC23B in pancreatic acinar function in adult mice. The Sec23bki/ko mice provide a novel model of chronic pancreatitis and growth retardation.
A common human missense mutation of vesicle coat protein SEC23B leads to growth restriction and chronic pancreatitis in mice
