PNKP – Ataxia with Oculomotor Apraxia Type 4

Ataxia with oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, oculomotor apraxia, peripheral neuropathy and dystonia. It is caused by biallelic pathogenic variants in the polynucleotide kinase 3′-phosphatase gene PNKP (HGNC:9154), which encodes a dual‐function enzyme essential for DNA 5′-kinase and 3′-phosphatase activities in strand break repair.

By whole exome sequencing, a 27-year-old German woman with clinical AOA4 and cerebellar pilocytic astrocytoma was found to harbor two compound heterozygous truncating PNKP variants: c.1253_1269dup (p.Thr424fs) and c.1545C>G (p.Tyr515Ter) (PMID:29498415). Both variants localize within the kinase domain and are predicted to ablate kinase activity and truncate the C-terminal region of the protein.

The duplication c.1253_1269dup (p.Thr424fs) has been recurrently observed in AOA4 cases and leads to a frameshift in exon 14 resulting in a premature stop codon 49 residues downstream (PMID:29498415). The novel nonsense variant c.1545C>G (p.Tyr515Ter) predicts loss of the final seven C-terminal amino acids, confirming a loss-of-function mechanism.

Functional characterization of a conserved glutamine mutation in AOA4 patient‐derived cells demonstrated abrogated nuclear import of mutant PNKP, accumulation of DNA double-strand breaks and chronic activation of the DNA damage response, highlighting impaired nuclear localization as a key pathogenic mechanism (PMID:37061005).

No conflicting evidence has been reported to date, and PNKP‐deficient cellular and animal models recapitulate the neurodegenerative and DNA repair defects seen in patients, reinforcing the causative link between PNKP loss of function and AOA4.

In summary, autosomal recessive truncating variants in PNKP underlie AOA4 through loss of DNA end-processing activity and defective DNA repair. Genetic testing of PNKP in individuals presenting with cerebellar ataxia and oculomotor apraxia enables definitive diagnosis and informs clinical management.

References

• Clinical genetics • 2018 • Rare compound heterozygous variants in PNKP identified by whole exome sequencing in a German patient with ataxia-oculomotor apraxia 4 and pilocytic astrocytoma. PMID:29498415
• The Journal of biological chemistry • 2023 • Functional analysis of a conserved site mutation in the DNA end processing enzyme PNKP leading to ataxia with oculomotor apraxia type 4 in humans. PMID:37061005

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