Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin

In eukaryotic cells, newly synthesized secretory proteins require COPII (coat protein complex II) to exit the endoplasmic reticulum (ER). COPII contains five core components: SAR1, SEC23, SEC24, SEC13, and SEC31. SEC23 is a GTPase-activating protein that activates the SAR1 GTPase and also plays a role in cargo recognition. Missense mutations in the human COPII paralogues SEC23A and SEC23B result in craniolenticulosutural dysplasia and congenital dyserythropoietic anemia type II, respectively. We now report that mice completely deficient for SEC23B are born with no apparent anemia phenotype, but die shortly after birth, with degeneration of professional secretory tissues. In SEC23B-deficient embryonic pancreas, defects occur in exocrine and endocrine tissues shortly after differentiation. Pancreatic acini are completely devoid of zymogen granules, and the ER is severely distended. Similar ultrastructural alterations are also observed in salivary glands, but not in liver. Accumulation of proteins in the ER lumen activates the proapoptotic pathway of the unfolded protein response, suggesting a central role for apoptosis in the degeneration of these tissues in SEC23B-deficient embryos. Although maintenance of the secretory pathway should be required by all cells, our findings reveal a surprising tissue-specific dependence on SEC23B for the ER exit of highly abundant cargo, with high levels of SEC23B expression observed in professional secretory tissues. The disparate phenotypes in mouse and human could result from residual SEC23B function associated with the hypomorphic mutations observed in humans, or alternatively, might be explained by a species-specific shift in function between the closely related SEC23 paralogues. mammalian embryo abnormalities | vesicular transport protein | genetics | secretory granules | pancreatitis I n eukaryotic cells, secreted proteins and proteins that are targeted to the plasma membrane and internal organelles are synthesized in the endoplasmic reticulum (ER) and sorted through the secretory pathway. This process has been extensively studied, particularly in budding yeast (1). Proteins destined to traffic from the ER to the Golgi are packaged into COPII (coat protein complex II)-coated vesicles (2-4). COPII is composed of at least five proteins, a small GTPase SAR1 and two cytosolic protein complexes, SEC23-SEC24 and SEC13-SEC31 (5). The GTP-bound form of SAR1 binds to the ER membrane and recruits the SEC23-SEC24 heterodimer to form the "prebudding complex," which in turn recruits the outer coat composed of SEC13-SEC31 heterotetramers to complete the COPII coat structure (6).The COPII complex captures cargo into vesicles and mediates vesicle budding from the ER. Cargo recognition appears to be mediated primarily by the SEC24 subunit, which recognizes divergent export signals located in the cytosolic domain of cargo proteins (7,8). SEC23 and SAR1 also play a role in the recognition of at least a subset of cargos (9, 10). SEC23 is a GTPaseactivating protein (GAP) that activates the SAR1...

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“…Timed matings were performed as previously described (43). The morning after copulation plug was observed is designated as E0.5.…”

Section: Methodsmentioning

confidence: 99%

“…TUNEL staining was performed according to the manufacturer's instructions (Roche Diagnostics). X-gal staining for β-gal activity and immunofluorescence staining of MEFs were performed as previously described (43). Images were visualized and captured with an Olympus FluoView confocal microscope.…”

Section: Methodsmentioning

confidence: 99%

SEC23B is required for the maintenance of murine professional secretory tissues

Tao

Zhu

Wang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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105

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“…22,23 We previously reported a genetically engineered mouse carrying a gene-trap interruption of the Lman1 gene. 24 Mice homozygous for this gene-trap allele (Lman1 gt1/gt1 ) exhibit reduced FV and FVIII levels that are ;50% of normal, in contrast to the ;10% to 15% levels in human F5F8D patients. As expected, this modest reduction in FV and FVIII results in a much milder phenotype than reported for hemophilia A mice carrying a F8 gene-targeted allele leading to complete absence of FVIII.…”

Section: Introductionmentioning

confidence: 99%

Murine coagulation factor VIII is synthesized in endothelial cells

Everett

Cleuren

Khoriaty³

et al. 2014

Blood

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166

145

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• Lman1 tissue-specific knockout mice reveal that endothelial cells, not hepatocytes, are the primary source of FVIII biosynthesis.• F8 gene expression is heterogeneous among endothelial cell populations in different tissues.The primary cellular source of factor VIII (FVIII) biosynthesis is controversial, with contradictory evidence supporting an endothelial or hepatocyte origin. LMAN1 is a cargo receptor in the early secretory pathway that is responsible for the efficient secretion of factor V (FV) and FVIII to the plasma. Lman1 mutations result in combined deficiency of FV and FVIII, with levels of both factors reduced to ∼10% to 15% of normal in human patients. We generated Lman1 conditional knockout mice to characterize the FVIII secretion profiles of endothelial cells and hepatocytes. We demonstrate that endothelial cells are the primary biosynthetic source of murine FVIII and that hepatocytes make no significant contribution to the plasma FVIII pool. Utilizing RiboTag mice and polyribosome immunoprecipitation, we performed endothelial cell-specific messenger RNA isolation and quantitative polymerase chain reaction analyses to confirm that endothelial cells highly express F8 and to explore the heterogeneity of F8 expression in different vascular beds. We demonstrate that endothelial cells from multiple, but not all, tissues contribute to the plasma FVIII pool in the mouse. (Blood. 2014;123(24):3697-3705)

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“…LMAN1-deficient mice demonstrate decreased FV and FVIII levels (ϳ 50% of normal), and slightly distended ER with accumulation of ␣1-antitrypsin in hepatocytes, though ␣1-antitrypsin plasma levels are not reduced. 9 …”

Section: Pathogenesis Of F5f8dmentioning

confidence: 99%

The COPII pathway and hematologic disease

Khoriaty

Vasievich

Ginsburg

2012

Blood

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IntroductionMultiple human diseases resulting from defects in the endoplasmic reticulum (ER)-to-Golgi transport have been reported over the past 14 years (Table 1). Anderson disease or chylomicron retention disorder (CMRD), 1 a disease characterized by malabsorption of lipids from the diet and accumulation of chylomicrons in the enterocytes, results from mutations in SAR1B, a component of coat protein complex II (COPII)-coated vesicles that bud from the surface of the ER and transport cargo proteins to the Golgi apparatus. Patients with CMRD exhibit failure to thrive in infancy, absence of circulating chylomicrons, low levels of plasma cholesterol, and deficiency of fat-soluble vitamins. Mutations in SEC23A, another component of the COPII coat, result in cranio-lenticulosutural-dysplasia (CLSD), 2 an autosomal recessive syndrome characterized by sutural cataracts, late closure of the cranial fontanelles, skeletal abnormalities, and dysmorphic facial features. Only 2 CLSD pedigrees have been reported, each with a different missense mutation. 2,3 Defects in the ER export machinery have been reported to cause 2 hematologic diseases, combined deficiency of coagulation factors V (FV) and VIII (FVIII) (F5F8D) and congenital dyserythropoietic anemia type II (CDAII). F5F8D is characterized by a decrease in FV and FVIII levels to ϳ 10% of normal with generally mild bleeding manifestations. This disorder results from mutations in either LMAN1 4 (lectin mannose-binding protein 1) or MCFD2 5 (multiple coagulation factor deficiency protein 2), 2 genes that encode the components of a specific ER cargo receptor for FV and FVIII. CDAII results from mutation in SEC23B, a paralog of SEC23A in mammals. CDAII is characterized by mild to moderate anemia, bi-or multinucleated erythroblasts, aberrant glycosylation of erythrocyte band 3, and red blood cell (RBC) lysis in some (but not all) acidified normal sera.Although no human diseases resulting from defects in other components of the early secretory pathway have been reported to date, animal models of defects in Sec24B, Sec24C, and Sec24D, have been described [6][7][8] (Table 1), again reflecting a range of manifestations, from no apparent phenotype (zebrafish Sec24C), 8 to a unique neural tube developmental defect (murine Sec24B) 7,12 to characteristic skeletal malformations (zebrafish Sec24D). 8 A general overview of the Mendelian disorders resulting from defects in the membrane trafficking machinery was recently published. 13 In this review, we focus on the 2 hematologic diseases F5F8D indicates combined deficiency of coagulation factors V and VIII; CMRD, chylomicron retention disorder; CLSD, cranio-lenticulo-sutural-dysplasia; CDAII, congenital dyserythropoietic anemia type II; and NR, none reported.*Morphant zebrafish models (where the zebrafish have been treated with a morpholino antisense oligonucleotide to "knockdown" the expression of the gene of interest). †Mutant zebrafish models. 31BLOOD, 5 JULY 2012 ⅐ VOLUME 120, NUMBER 1For personal use only. on April 28, 2019. by gue...

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Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin

Cited by 51 publications

References 49 publications

SEC23B is required for the maintenance of murine professional secretory tissues

SEC23B is required for the maintenance of murine professional secretory tissues

Murine coagulation factor VIII is synthesized in endothelial cells

The COPII pathway and hematologic disease

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