Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein

Abstract

CDA type I is a rare hereditary anemia, characterized by relative reticulocytopenia, and congenital anomalies. It is caused by biallelic mutations in one of the two genes: (i) CDAN1 , encoding Codanin-1, which is implicated in nucleosome assembly and disassembly; (ii) C15orf41 , which is predicted to encode a divalent metal ion-dependent restriction endonuclease with a yet unknown function. We described two cases of CDA type I, identifying the novel variant, Y94S, in the DNA binding domain of C15orf41, and the H230P mutation in the nuclease domain of the protein. We first analyzed the gene expression and the localization of C15orf41. We demonstrated that C15orf41 and CDAN1 gene expression is tightly correlated, suggesting a shared mechanism of regulation between the two genes. Moreover, we functionally characterized the two variants, establishing that the H230P leads to reduced gene expression and protein level, while Y94S induces a slight decrease of expression. We demonstrated that C15orf41 endogenous protein exhibits nuclear and cytosolic localization, being mostly in the nucleus. However, no altered nuclear-cytosolic compartmentalization of mutated C15orf41 was observed. Both mutants accounted for impaired erythroid differentiation in K562 cells, and H230P mutant also exhibits an increased S-phase of the cell cycle in these cells. Our functional characterization demonstrated that the two variants have different effects on the stability of the mutated mRNA, but both resulted in impaired erythroid maturation, suggesting the block of cell cycle dynamics as a putative pathogenic mechanism for C15orf41-related CDA I.

Characterization of the interactions between Codanin-1 and C15Orf41, two proteins implicated in congenital dyserythropoietic anemia type I disease

“…Quite counterintuitively, C15Orf41 exists in all taxa in which Codanin-1 exist, but not vice versa, suggesting that the major function of the presumptive scaffold protein, Codanin-1, is to regulate C15Orf41 activities. Additional support for common functions of these two proteins, is the recent report documenting a correlation between the levels of the two genes in different cell lines [29]. The characterization of these functions and their relation to erythrocyte developments should await further investigation.…”

Characterization of the interactions between Codanin-1 and C15Orf41, two proteins implicated in Congenital dyserythropoietic anemia type I disease

“…Quite counterintuitively, C15Orf41 exists in all taxa in which Codanin-1 exist, but not vice versa, suggesting that the major function of the presumptive scaffold protein, Codanin-1, is to regulate C15Orf41 activities. Additional support for common functions of these two proteins, is the recent report documenting a correlation between the levels of the two genes in different cell lines [28]. The characterization of these functions and their relation to erythrocyte developments should await further investigation.…”

Mild dyserythropoiesis and β-like globin gene expression imbalance due to the loss of histone chaperone ASF1B

“…It has been recognized that a special case of a genetic variant of KLF1 is causative of congenital dyserythropoietic anemia (CDA) variant (type IV) in addition to the accompanying HPFH already reported. Interestingly, the two genes involved in the development of CDA type I are CDAN1 and C15ORF41, both of which have been reported to physically interact with ASF1B [50][51][52][53][54][55]. This suggests that shared functions by the interacting proteins ASF1B, CDAN1, and C15ORF41 might be crucial during erythropoiesis and for β-like globin expression regulation.…”