Mutational survivorship bias: The case of PNKP
Por um escritor misterioso
Descrição
The molecular function of a protein relies on its structure. Understanding how variants alter structure and function in multidomain proteins is key to elucidate the generation of a pathological phenotype. However, one may fall into the logical bias of assessing protein damage only based on the variants that are visible (survivorship bias), which can lead to partial conclusions. This is the case of PNKP, an important nuclear and mitochondrial DNA repair enzyme with both kinase and phosphatase function. Most variants 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 tolerability to variation, we evaluated whether variants in PNKP are under survivorship bias. Here, we provide the evidence that supports a higher tolerance in the kinase domain even when all variants reported are deleterious. Instead, the phosphatase domain is less tolerant due to its lower variant rates, a higher degree of sequence conservation, lower dN/dS ratios, and the presence of more disease-propensity hotspots. Together, our results support previous experimental evidence that demonstrated that the phosphatase domain is functionally more necessary and relevant for DNA repair, especially in the context of the development of the central nervous system. Finally, we propose the term "Wald’s domain" for future studies analyzing the possible survivorship bias in multidomain proteins.
Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ
Browse Preprints - Authorea
Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain
Two patients with PNKP mutations presenting with microcephaly, seizure, and oculomotor apraxia - Taniguchi‐Ikeda - 2018 - Clinical Genetics - Wiley Online Library
Browse Preprints - Authorea
Mutational survivorship bias: The case of PNKP
Mutational survivorship bias: The case of PNKP
DNA repair Leaders in Pharmaceutical Business Intelligence (LPBI) Group
Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor
Frontiers Polyadenosine diphosphate-ribose polymerase inhibitors: advances, implications, and challenges in tumor radiotherapy sensitization
Molecular Radiation Biology
Mutational Survivorship Bias: The case of PNKP
Mutational survivorship bias: The case of PNKP
Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor
Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain
de
por adulto (o preço varia de acordo com o tamanho do grupo)
