PNKP – Microcephaly, Seizures, and Developmental Delay

Polynucleotide kinase/phosphatase (PNKP) is a bifunctional enzyme with DNA 3′-phosphatase and 5′-kinase activities critical for repair of single- and double-strand breaks. Biallelic loss-of-function variants in PNKP cause an autosomal recessive neurodevelopmental disorder characterized by congenital microcephaly, early-onset seizures, and global developmental delay (MCSZ) (PNKP, Microcephaly, Seizures, and Developmental Delay).

Initial genome-wide linkage in consanguineous pedigrees mapped MCSZ to chromosome 19q13.33 and identified PNKP mutations segregating with disease in multiple families. To date, over 36 unrelated probands have been reported with biallelic PNKP variants (PMID:20118933).

The variant spectrum includes missense, splice-site, frameshift and deep intronic alleles affecting both kinase and phosphatase domains. A recurrent missense variant, c.968C>T (p.Thr323Met), has been reported in compound heterozygosity and confirmed pathogenic by functional assays (PMID:37916443). Homozygous segregation was documented in at least 8 additional affected relatives in consanguineous kindreds (PMID:20118933).

Clinically, all patients present with congenital microcephaly, intractable early-onset seizures, and severe global developmental delay; additional features include callosal dysgenesis, intellectual disability, speech impairment, hyperactivity and ataxia (PMID:31707899).

Biochemical and cellular studies demonstrate that MCSZ-associated variants drastically reduce or abolish PNKP kinase/phosphatase activity, destabilize the protein, impair single- and double-strand break repair, and lead to PARP1 hyperactivation (PMID:22508754; PMID:31041400). These data support a loss-of-function mechanism.

No significant conflicting evidence has been reported. Integration of robust genetic segregation and concordant functional assays establishes a definitive gene–disease relationship. Key take-home: biallelic PNKP variants cause MCSZ, and PNKP genetic and enzymatic testing should be integrated into diagnostic workflows for early-onset microcephaly with seizures and developmental delay.

References

• Nature Genetics • 2010 • Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. PMID:20118933
• Scientific Reports • 2022 • Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor. PMID:35354845
• Nucleic Acids Research • 2012 • Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair. PMID:22508754
• Neurology: Genetics • 2019 • Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ. PMID:31041400
• Fetal and Pediatric Pathology • 2021 • Compound Heterozygous Mutations in PNKP Gene in an Iranian Child with Microcephaly, Seizures, and Developmental Delay. PMID:31707899
• Molecular Genetics & Genomic Medicine • 2024 • Novel PNKP mutations associated with reduced DNA single-strand break repair and severe microcephaly, seizures, and developmental delay. PMID:37916443

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