Fig. 2

Alignment of five EZH2 isoforms protein sequences (UniProt). SET domain is shown in green (Q15910-1 AA 612–727; Q15910-2 AA 617–732; Q15910-3 AA 573–688; Q15910-4 AA 603–718; Q15910-5 AA 561–676). Germline mutations [27] are shown in orange, “loss of function” mutations [42] in blue, and “gain of function” mutations [26, 30, 32, 33, 44] in red. All mutations listed in the cited references are marked on respective isoform sequences, highlighting the lack of uniformity in annotating mutations according to consensus sequence (Q15910-1). Therefore, mutation A677 (in isoform 1) is listed as somatic, activating mutation and at the same time, annotated as mutation A682 (in isoform 2), has been listed as germline mutation which was discovered in the Weaver syndrome patient who developed ALL and neuroblastoma in early childhood. This is in accord with the oncogenic potential of this mutation. Inactivating mutations R684 in isoform 2 (corresponding to R679 in isoform 1) and E745 in isoform 2 (corresponding to E740 in isoform 1) have been shown to be mutated in Weaver syndrome patients. None of the five patients with inherited mutation R684C (present as somatic mutation in one 82-year-old patient suffering from chronic myelomonocytic leukemia) developed malignant disease at the time of testing for germline mutation of EZH2. Germline mutation E745K (isoform 2) was present in a patient who developed non-Hodgkins lymphoma at the age of 13. Somatic mutation of this codon was detected in one patient with chronic myeloic leukemia during blast crisis.