PTPRT D1364Gfs*24 affects the second catalytic domain of the protein
The selected PTPRT mutation involves the insertion of a guanine between positions 4090 and 4091 of the cDNA (ENST00000373198) (Figure 1B), causing a shift in the reading frame that is translated as the addition of 23 erroneous amino acids followed by a premature stop codon. This alteration is located at the end of the gene, meaning the loss of the last 97 amino acids of the protein and affecting the second phosphatase domain (also known as D2), which is thought to be responsible for the regulation of the enzyme’s activity. Figure 2A shows the different protein domains of PTPRT, together with the location of the variant and a schematic visualization of the resulting mutant protein. The effect that the truncation is predicted to have on the 3D structure of PTPRT’s cytoplasmatic region (including the 2 catalytic domains) can be observed in Figure 2B, showing a considerable gap caused by the mutation. Finally, Figure 2C was adapted from Lui et al. (Lui et al., 2014) to show the effect of the mutation on the sequence of the D2 domain, pointing out those residues in direct contact with the phospho-tyrosine (in grey) that are lost with this mutation.
PTPRT D1364Gfs*24 segregation study
The result from the segregation study carried out in other family members is shown in Figure 1A. In addition to the two affected probands originally studied (II:6 and II:7), members II:4 and III:5 also carried the variant, while II:2, II:3 and II:5 showed a wild-type PTPRT . Positive members include one with CRC diagnosed at 70 (II:6), one with endometrial cancer diagnosed at 28 (II:7), one with breast cancer diagnosed at 66 (II:4) and a healthy but still young relative (III:5). The negative result was observed in two healthy elderly relatives (II:2 and II:5) and a CRC patient diagnosed at a very late age (II:3, diagnosed at 85).