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Mutations in the calreticulin gene:

Mutations in the calreticulin gene: CALR
At the end of 2013, frameshift mutations in the CALR gene were discovered in the majority of JAK2− and MPL− ET and PMF (50%-60% ET and 75% PMF).28,29 There are >50 mutations now described, but all are located in exon 9 inducing a +1 (−1+2) frameshift. At the time of writing, only the mutations leading to this +1 frameshift are known to be pathogenic. The other nonpathogenic mutations are usually germ line variants of CALR. Specific shifting of the reading frame leads to a new C terminus devoid of the KDEL motif, important for the protein retention in the endoplasmic reticulum (ER). The mutated CALR protein contains a common new amino acid sequence that bears positive charges. In contrast to wild-type (WT) CALR, the negative charges required for calcium binding are lost at different extents, depending on the mutant. The 2 most frequent mutations correspond to a 52-bp deletion (p.L367fs46), also called type 1 and a 5-bp insertion (p.K385fs47), also called type 2. They represent nearly the 2 extremes of modifications observed in exon 9: the del52 having lost most of the WT exon 9 sequence and calcium-binding sites, and ins5 being closer to the WT sequence having kept around 50% of negative charges. According to these structural changes, the other mutations have been classified as type 1–like and type 2–like using algorithms based on the preservation of an α helix close to WT in type 2–like mutation