The COPII pathway and hematologic disease

Abstract

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...

Transcriptional divergence and conservation of human and mouse erythropoiesis

“…Both SEC23B and SEC23A encode proteins that are critical components of the coat protein complex II (COPII) that is necessary for endoplasmic-reticulum-to-Golgi-complex transport of secretory vesicles (35). In humans, recessive mutations of SEC23B cause congenital dyserythropoietic anemia (CDA) type II (10,36). Although the exact basis for the pathophysiology of this disease is not understood, erythroid cells are thought to be particularly sensitive to mutations in SEC23B due to the lack of expression of SEC23A, which can compensate for the loss of SEC23B in other tissues (10).…”

Characteristic phenotypes associated with congenital dyserythropoietic anemia (type II) manifest at different stages of erythropoiesis

“…Clinically, patients present with typical symptoms associated with hemolytic anemia of variable degree, erythroid hyperplasia, splenomegaly, gallstones and iron overload. [1][2][3] Other characteristic features of CDAII include erythrocytes with hypoglycosylated membrane proteins including band 3, and the glucose transporter Glut1 [4][5][6][7] and a "double plasma membrane" due to residual endoplasmic reticulum, that stains positively for endoplasmic reticulum (ER) protein markers GRP78, calreticulin and protein disulfide isomerase (PDI). 8 The stage at which the characteristic features of CDAII observed in patients' erythrocytes manifest during erythropoiesis is currently unknown.…”

Absence of a Red Blood Cell Phenotype in Mice with Hematopoietic Deficiency of SEC23B

“…ongenital dyserythropoietic anemia type II (CDAII), also known as hereditary erythroblastic multinuclearity with a positive acidified serum lysis test (HEMPAS), is an autosomal recessive disease characterized clinically by mild to moderate anemia resulting from ineffective erythropoiesis (median hemoglobin, 9.1 to 9.8 g/dl), the presence of bi/multinucleated erythroblasts in the bone marrow (BM), jaundice from indirect hyperbilirubinemia, and splenomegaly (1,2). CDAII is distinguished from other congenital anemias by a characteristic double-membrane appearance in red blood cell (RBC) electron microscopy resulting from the residual endoplasmic reticulum (ER) (3), a faster-migrating and narrower band on SDS-PAGE for the RBC membrane protein band 3, and lysis of RBCs in some, but not all, acidified normal sera (Ham's test) (1,2).…”

“…CDAII is distinguished from other congenital anemias by a characteristic double-membrane appearance in red blood cell (RBC) electron microscopy resulting from the residual endoplasmic reticulum (ER) (3), a faster-migrating and narrower band on SDS-PAGE for the RBC membrane protein band 3, and lysis of RBCs in some, but not all, acidified normal sera (Ham's test) (1,2).…”

“…SEC23 is a core component of the coat protein complex II (COPII)-coated vesicles that transport cargo proteins from the ER to the Golgi apparatus (2,5). More than 60 different SEC23B mutations have been identified in CDAII patients (4,(6)(7)(8)(9)(10)(11)(12)(13)(14), affecting every domain of the protein (7).…”