Figure 1.

Missense variants and conservation of the PWWP domain of DNMT3A. (a) Representation of DNMT3A missense variants affecting the PWWP domain. Upper part, gain-of-function germline variants (denoted with a grey box) reported in patients with PPGL or microcephalic dwarfism. Bottom part, somatic variants reported in COSMIC (https://cancer.sanger.ac.uk/cosmic) and/or cBioPortal (www.cbioportal.org) databases affecting the same amino acids found mutated in the mentioned patients and/or affecting other residues involved in the aromatic cage [16,20] (denoted in red letters). (b) Multiple-sequence alignment of PWWP domains performed with Clustal Omega (European Bioinformatics Institute, Cambridge, UK). The alignment includes at least a member of each of the six classes of human PWWP domains since DNMT3A and DNMT3B share the same class (DNMT3B related) and PWWP3A and HDGF are also included in the same class (HDGF related) [20]. The position of DNMT3A-Gly332 is denoted with a green box.