A complex comprising C15ORF41 and Codanin-1: the products of two genes mutated in congenital dyserythropoietic anaemia type I (CDA-I).

John Rouse,Rachel Toth,Axel Knebel,Maithili Shroff

doi:10.1042/bcj20190944

Abstract

Congenital dyserythropoietic anaemia (CDA) type I is a rare blood disorder characterised by moderate to severe macrocytic anaemia and hepatomegaly, with spongy heterochromatin and inter-nuclear bridges seen in bone marrow erythroblasts. The vast majority of cases of CDA type I are caused by mutations in the CDAN1 gene. The product of CDAN1 is Codanin-1, which interacts the histone chaperone ASF1 in the cytoplasm. Codanin-1 is a negative regulator of chromatin replication, sequestering ASF1 in the cytoplasm, restraining histone deposition and thereby limiting DNA replication. The remainder of CDA-I cases are caused by mutations in the C15ORF41 gene, but very little is known about the product of this gene. Here, we report that C15ORF41 forms a tight, near-stoichiometric complex with Codanin1 in human cells, interacting with the C-terminal region of Codanin-1. We present the characterisation of the C15ORF41–Codanin-1 complex in humans in cells and in vitro, and demonstrate that Codanin-1 appears to sequester C15ORF41 in the cytoplasm as previously shown for ASF1. The findings in this study have major implications for understanding the functions of C15ORF41 and Codanin-1, and the aetiology of CDA-I.

Highlights

Congenital dyserythropoietic anaemia (CDA) represents a heterogeneous group of rare autosomal recessive hereditary disorders characterised by distinct morphological abnormalities of erythroid precursors in the bone marrow, ineffective erythropoiesis and suboptimal reticulocyte count resulting from inadequate marrow response [1,2]
CDA-III is an autosomal dominant disorder that results from mutations in the KIF23 gene [9]
We demonstrated that C15ORF41 interacts with Codanin-1 when overexpressed, and at the endogenous level; in this light, C15ORF41 has been designated the symbol CDAN1 interacting protein 1 (CDIN1) for CDAN1 interacting nuclease 1 by the HUGO Gene Nomenclature Committee (HNGC)

Summary

Introduction

Congenital dyserythropoietic anaemia (CDA) represents a heterogeneous group of rare autosomal recessive hereditary disorders characterised by distinct morphological abnormalities of erythroid precursors in the bone marrow, ineffective erythropoiesis and suboptimal reticulocyte count resulting from inadequate marrow response [1,2]. CDA type II is the most prevalent form of CDA and is characterised by jaundice, hepatosplenomegaly, gallstones, normocytic anaemia and an iron overload [5,6,7]. This disease is inherited in an autosomal recessive manner, due to mutation in the SEC23B gene that encodes for the component of the coat protein complex II (COPII). CDA-III is an autosomal dominant disorder that results from mutations in the KIF23 gene [9]. CDA-IV is an autosomal dominant disorder, caused by mutation in the KLF1 gene which encodes for a transcription factor involved in the regulation of erythrocyte development [4]

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