CALR gene. (A) Calreticulin (CALR) domain structure. CALR protein has three distinctive domains (N, P, C). The P-domain is involved in the chaperone function. The C-domain is rich in acidic amino acids and contains the high capacity, low affinity calcium binding site. The last four C-terminal amino acids (KDEL) are the endoplasmic reticulum retention signal. (B) Variability of CALR exon 9 insertion/deletion mutations found in MPN. Type 1 and type 2 mutations are most frequent and together they are present in over 85% of CALR mutated cases. (C) Impact of MPN associated mutations on CALR protein structure. Despite the diversity of mutations found in the CALR gene exon 9, the impact on the protein structure is very similar. The two most common CALR insertion/deletion mutations found in MPN (type 1 and type 2) are shown, which frameshift to the same alternative reading frame. This results in a novel C-terminus of the mutant CALR that turns into a positively charged peptide lacking the calcium binding and KDEL regions.