Inherited hematological disorders due to defects in coat protein (COP)II complex

Abstract

Many diseases attributed to trafficking defects are primary disorders of protein folding and assembly. However, an increasing number of disease states are directly attributable to defects in trafficking machinery. In this context, the cytoplasmic coat protein (COP)II complex plays a pivotal role: it mediates the anterograde transport of correctly folded secretory cargo from the endoplasmic reticulum towards the Golgi apparatus. This review attempts to describe the involvement of COPII complex alteration in the pathogenesis of human genetic disorders; particularly, we will focus on two disorders, the Congenital Dyserythropoietic Anemia type II and the Combined Deficiency of Factor V and VIII. Am. J. Hematol., 88:135–140, 2013. © 2012 Wiley Periodicals, Inc.

Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II

“…Anemia of variable degree, jaundice and splenomegaly are common clinical findings [1]. This condition belongs to COPII-related human genetic disorders [2]. It is due to mutations in SEC23B (chr 20p11.23), a component of COPII complex, the core trafficking machinery of the endoplasmic reticulum-Golgi [3].…”

COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis

“…However, there are several examples of human disorders in which widely expressed proteins lead to distinct clinical phenotypes 34,35 . For instance, four Mendelian syndromes characterized by disparate clinical phenotypes have been described that involve mutations in the COPII trafficking machinery 36 . It remains unclear in these disorders and in patients with COPA mutations why only certain organ systems are affected.…”

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

“…9,10 Since then approximately 60 different causative mutations have been described along the gene including missense, nonsense, deletion and splice site mutations; 11 the missense mutations affecting highly conserved residues in multiple domains of SEC23B. [9][10][11][12][13][14][15][16][17] The defect is transmitted as an autosomal recessive trait; in almost all patients, mutations are detected at homozygous or compound heterozygote level. The coexistence of two severe nonsense mutations has never been described suggesting that this condition is most likely lethal.…”