ATRX mutations identified in cancer are frequently nonsense and frameshift mutations that result in premature protein truncation. Mutant ATRX proteins are usually undetectable in the nucleus (Jiao et al. 2011). Missense mutants of ATRX have not been functionally tested in the context of the full length protein (Jiao et al. 2011). ATRX likely contains two DAXX-binding modules. The module mapping to amino acids 1189-1326 strongly binds to DAXX and is thought to be the main DAXX interaction domain. The module mapping to amino acids 321-865 weakly binds to DAXX (Tang et al. 2004), if at all (Wang et al. 2017). A truncation mutant of ATRX that consists of the N-terminal 338 amino acids, generated by directed mutagenesis, does not bind to DAXX (Tang et al. 2004). The minimal portion of ATRX that can, on its own, interact with DAXX involves amino acids 1253-1326 (Wang et al. 2017). Some ATRX missense mutants have been functionally evaluated in the context of the fragment that consists of amino acids 1253-1326 (Wang et al. 2017), but are not shown here. All ATRX truncation mutants in which the stop codon occurs upstream of the amino acid 339 are annotated as loss-of-function mutants. These include the following nonsense mutants:
ATRX E63*
ATRX S79*
ATRX G161*
ATRX Q176*
ATRX Q177*
ATRX Y187*
ATRX R188*
ATRX Q193*
ATRX S213*
ATRX W222*
ATRX R250*
ATRX L253*
ATRX W263*
ATRX Y266*
ATRX E288*
ATRX Q292*
ATRX K319*
and the following frameshift mutants:
ATRX A23Hfs*18
ATRX S112Qfs*15
ATRX G124Vfs*3
ATRX R160Pfs*29
ATRX H166Mfs*4
ATRX Q176Hfs*13
ATRX D184Ifs*22
ATRX P190Hfs*15
ATRX Y204*
ATRX M205*
ATRX C268Qfs*18
ATRX L273Ffs*9
ATRX L274Ffs*8
ATRX K329Ifs*3
ATRX K330Nfs*2.
All ATRX truncation mutants that lack the second DAXX-binding module are annotated as candidate loss-of-function mutants. These include the following nonsense mutants of ATRX:
ATRX Y341*
ATRX Q391*
ATRX E431*
ATRX K455*
ATRX K459*
ATRX E482*
ATRX E533*
ATRX Q545*
ATRX G551*
ATRX S567*
ATRX E585*
ATRX E625*
ATRX E643*
ATRX R666*
ATRX E680*
ATRX Q727*
ATRX S729*
ATRX S750*
ATRX R781*
ATRX K782*
ATRX S788*
ATRX R808*
ATRX K823*
ATRX K826*
ATRX K967*
ATRX K983*
ATRX Q984*
ATRX K1052*
ATRX E1065*
ATRX G1071*
ATRX S1101*
ATRX E1119*
ATRX E1159*
and the following frameshift mutants of ATRX:
ATRX S342*
ATRX K358Nfs*2
ATRX L359Hfs*3
ATRX L359Tfs*3
ATRX I360Rfs*6
ATRX I383Nfs*11
ATRX T387Qfs*27
ATRX K425Rfs*8
ATRX N428Yfs*5
ATRX L452Ffs*12
ATRX S471Vfs*43
ATRX V478Ffs*36
ATRX L513*
ATRX T534Wfs*3
ATRX Q554Rfs*21
ATRX S558Ifs*4
ATRX K562*
ATRX L639Wfs*10
ATRX P663Yfs*10
ATRX L664*
ATRX N676Kfs*17
ATRX T684Sfs*2
ATRX E723Dfs*9
ATRX V725Gfs*7
ATRX I737Kfs*3
ATRX L738Gfs*13
ATRX S747Ffs*6
ATRX S747Rfs*6
ATRX D774Mfs*29
ATRX K778Nfs*23
ATRX S784Lfs*13
ATRX D791*
ATRX T792Ifs*12
ATRX S797*
ATRX K823Rfs*7
ATRX A834Pfs*35
ATRX R840Efs*29
ATRX R840Kfs*9
ATRX T844Yfs*5
ATRX G859Efs*10
ATRX G859Rfs*4
ATRX S871Hfs*34
ATRX S876Lfs*29
ATRX Q883Rfs*13
ATRX R885Sfs*21
ATRX E886Dfs*10
ATRX E886Lfs*18
ATRX F888Sfs*17
ATRX K910*
ATRX K945Rfs*25
ATRX V957Sfs*7
ATRX K971Tfs*31
ATRX E976Dfs*2
ATRX E991Gfs*9
ATRX K993Rfs*10
ATRX K994Efs*6
ATRX P995Tfs*5
ATRX K1001Nfs*3
ATRX V1002*
ATRX E1010Mfs*24
ATRX E1017Dfs*5
ATRX K1018Rfs*5
ATRX K1045*
ATRX I1049*
ATRX I1049Kfs*69
ATRX I1049Mfs*3
ATRX I1049Nfs*4
ATRX K1057Rfs*61
ATRX K1081Rfs*37
ATRX D1106Ifs*12
ATRX C1122Lfs*8
ATRX D1126Rfs*3
ATRX R1128Sfs*2
ATRX K1143Rfs*47
ATRX T1172Lfs*18.