Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease

Abstract

A variety of human neurologic diseases are caused by inherited defects in DNA repair. In many cases, these syndromes almost exclusively impact the nervous system, underscoring the critical requirement for genome stability in this tissue. A striking example of this is defective enzymatic activity of polynucleotide kinase-phosphatase (PNKP), leading to microcephaly or neurodegeneration. Notably, the broad neural impact of mutations in PNKP can result in markedly different disease entities, even when the inherited mutation is the same. For example microcephaly with seizures (MCSZ) results from various hypomorphic PNKP mutations, as does ataxia with oculomotor apraxia 4 (AOA4). Thus, other contributing factors influence the neural phenotype when PNKP is disabled. Here we consider the role for PNKP in maintaining brain function and how perturbation in its activity can account for the varied pathology of neurodegeneration or microcephaly present in MCSZ and AOA4 respectively.

The polynucleotide kinase 3′-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25

“…It acts as a 5′-kinase/3′-phosphatase to create 5′-phosphate/3′-hydroxyl termini, which are a necessary prerequisite for ligation during repair [5]. Homozygous variants in this gene were previously linked to progressive cerebellar atrophy and polyneuropathy [6] and recently, to both severe ataxia with oculomotor apraxia 4 (AOA4, MIM 616267) or microcephaly with seizures and developmental delay (MCSZ, MIM 613402) [7]. Our findings imply that this DNA repair enzyme is involved in a broader phenotype, including a mild axonal peripheral polyneuropathy.…”

A Novel Homozygous Variant in the Fork-Head-Associated Domain of Polynucleotide Kinase Phosphatase in a Patient Affected by Late-Onset Ataxia With Oculomotor Apraxia Type 4

“…The pedigree of the proband's family is shown in Figure 1A. After genetic counseling, written informed consent was obtained, and clinical exome sequencing (4,800 human genes) was performed including 100 genes related to Ataxia and or Spastic Paraplegia (Clinical Exome Solution, SOPHiA genetics) on MiSeq platform (Illumina) (16).…”

Genome integrity and disease prevention in the nervous system

“…Mutations in PNKP can result in different neurologic disease characterized by either microcephaly or neurodegeneration. parents developed both microcephaly and ataxia but had mutations identical to those of individuals with MCSZ who did not develop ataxia; thus, it is likely that genetic modifiers influence the outcome of PNKP mutations (Poulton et al 2013;Dumitrache and McKinnon 2017).…”