A common human missense mutation of vesicle coat protein SEC23B leads to growth restriction and chronic pancreatitis in mice
| Autor: | Wei Wei, Zhigang Liu, Chao Zhang, Rami Khoriaty, Min Zhu, Bin Zhang |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
CDAII
congenital dyserythropoietic anemia type II ZG zymogen granule Mutation Missense Vesicular Transport Proteins TCA trichloroacetic acid Biochemistry ER endoplasmic reticulum Mice COPII coat protein complex II Larone syndrome Pancreatitis Chronic Neo neomycin Animals COPII pancreas TNF-α tumor necrosis factor alpha IGF-1 insulin-like growth factor 1 TEM transmission electron microscopy Molecular Biology Anemia Dyserythropoietic Congenital TUNEL terminal deoxynucleotidyl transferase dUTP nick-end labeling ES embryonic stem RBC red blood cell Cell Biology GH growth hormone IL interleukin secretion dyserythropoietic anemia STAT signal transducer and activator of transcription Phenotype GHR growth hormone receptor KI knockin Socs3 suppressor of cytokine signaling-3 growth hormone GTT glucose tolerance test ER stress JAK Janus kinase Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.101536 |
| Popis: | SEC23B is one of two vertebrate paralogs of SEC23, a key component of the coat protein complex II vesicles. Complete deficiency of SEC23B in mice leads to perinatal death caused by massive degeneration of professional secretory tissues. However, functions of SEC23B in postnatal mice and outside professional secretory tissues are unclear. In this study, we generated a Sec23b KO mouse and a knockin (KI) mouse with the E109K mutation, the most common human mutation in congenital dyserythropoietic anemia type II patients. We found that E109K mutation led to decreases in SEC23B levels and protein mislocalization. However, Sec23bki/ki mice showed no obvious abnormalities. Sec23b hemizygosity (Sec23bki/ko) was partially lethal, with only half of expected hemizygous mice surviving past weaning. Surviving Sec23bki/ko mice exhibited exocrine insufficiency, increased endoplasmic reticulum stress and apoptosis in the pancreas, and phenotypes consistent with chronic pancreatitis. Sec23bki/ko mice had mild to moderate anemia without other typical congenital dyserythropoietic anemia type II features, likely resulting from exocrine insufficiency. Moreover, Sec23bki/ko mice exhibited severe growth restriction accompanied by growth hormone (GH) insensitivity, reminiscent of Laron syndrome. Growth restriction is not associated with hepatocyte-specific Sec23b deletion, suggesting a nonliver origin of this phenotype. We propose that inflammation associated with chronic pancreatic deficiency may explain GH insensitivity in Sec23bki/ko mice. Our results reveal a genotype–phenotype correlation in SEC23B deficiency and indicate that pancreatic acinar is most sensitive to SEC23B deficiency in adult mice. The Sec23bki/ko mice provide a novel model of chronic pancreatitis and growth retardation with GH insensitivity. |
| Databáze: | OpenAIRE |
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