The molecular function of a protein relies on its structure.
Understanding how mutations alter structure and function in multi-domain
proteins, is key to elucidate how a pathological phenotype is generated.
However, one may fall into the logical bias of assessing protein damage
only based on the mutations that are viable (survivorship bias), which
can lead to partial conclusions. This is the case of PNKP, an important
nuclear and mitochondrial DNA repair enzyme with kinase and phosphatase
function. Most mutations in PNKP are confined to the kinase domain,
leading to a pathological spectrum of three apparently distinct clinical
entities. Since proteins and domains may have a different tolerance to
disease causing mutations, we evaluated whether mutations in PNKP are
under survivorship bias. Even when all mutations in the kinase domain
are deleterious, we found a mayor mutation tolerability landscape in
terms of survival. Instead, the phosphatase domain is less tolerant due
to its low mutation rates, higher degree of sequence conservation, lower
dN/dS ratios, and more disease-propensity hotspots. Thus, in
multi-domain proteins, we propose the term “Wald’s domain” for those
who are not apparently more associated with disease, but that are less
resistant to mutations in terms of survival.