Mutations in PNKP cause microcephaly, seizures and defects in DNA repair

Shen, Jun; Gilmore, Edward C.; Marshall, Christine A; Haddadin, Mary; Reynolds, John J.; Eyaid, Wafaa; Bodell, Adria; Barry, Brenda J.; Gleason, Danielle; Allen, Kristina M.; Ganesh, Vijay; Chang, Bernard S.; Grix, Arthur; Hill, Robert S.; Topçu, Meral; Caldecott, Keith W.; Barkovich, A. James; Walsh, Christopher A.

doi:10.1038/ng.526

Cited by 264 publications

(323 citation statements)

References 27 publications

(29 reference statements)

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“…No mutations were identified in XLF, LIGIV, or XRCC4, however. Additionally, the MRI images and the neurological features in this patient bore similarities to those previously seen in children with PNKP mutations (44). DNA-PK, as well as ataxia-telangiectasia mutated (ATM), phosphorylate PNKP (45), and PNKP functions during NHEJ, although it also functions in single-strand break repair.…”

Section: Discussionsupporting

confidence: 69%

PRKDC mutations in a SCID patient with profound neurological abnormalities

Woodbine¹,

Neal²,

Sasi³

et al. 2013

J. Clin. Invest.

133

134

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The DNA-dependent protein kinase catalytic subunit (DNA-PKcs; encoded by PRKDC) functions in DNA non-homologous end-joining (NHEJ), the major DNA double strand break (DSB) rejoining pathway. NHEJ also functions during lymphocyte development, joining V(D)J recombination intermediates during antigen receptor gene assembly. Here, we describe a patient with compound heterozygous mutations in PRKDC, low DNA-PKcs expression, barely detectable DNA-PK kinase activity, and impaired DSB repair. In a heterologous expression system, we found that one of the PRKDC mutations inactivated DNA-PKcs, while the other resulted in dramatically diminished but detectable residual function. The patient suffered SCID with reduced or absent T and B cells, as predicted from PRKDC-deficient animal models. Unexpectedly, the patient was also dysmorphic; showed severe growth failure, microcephaly, and seizures; and had profound, globally impaired neurological function. MRI scans revealed microcephaly-associated cortical and hippocampal dysplasia and progressive atrophy over 2 years of life. These neurological features were markedly more severe than those observed in patients with deficiencies in other NHEJ proteins. Although loss of DNA-PKcs in mice, dogs, and horses was previously shown not to impair neuronal development, our findings demonstrate a stringent requirement for DNA-PKcs during human neuronal development and suggest that high DNA-PK protein expression is required to sustain efficient pre-and postnatal neurogenesis. Introduction DNA nonhomologous end-joining (NHEJ) represents the major DNA double strand break (DSB) repair process in mammalian cells (1, 2). Thus, cells, mice, and patients defective in NHEJ proteins show markedly reduced DSB repair and radiosensitivity. NHEJ also functions during immune development due to its requisite role in V(D)J recombination (3). V(D)J recombination mediates immunoglobulin and T cell receptor gene assembly from variable (V), diversity (D), and joining (J) gene segments. Recombination is initiated by the RAG1/2 endonuclease, which introduces DSBs at recombination signal sequences (RSSs). The DNA ends, including the sequences encoding the antigen receptors (termed coding ends), have hairpinned termini; the RSSs are blunt ended. Rejoining of these recombination intermediates requires NHEJ proteins. Consequently, NHEJ defects in animals and humans causes SCID with reduced or absent T and B cells.6 core NHEJ components assemble as 2 complexes (1). The Ku70/80 heterodimer is the DNA double-stranded (ds) end recognition protein, binding DNA ds ends with high affinity. Ku recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs; encoded by PRKDC), generating the DNA-PK holoenzyme. The DNA-PK complex prevents unbridled exonuclease digestion of DNA ends, enhances appropriate end-processing, and recruits the ligation complex, which encompasses XRCC4,

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Section: Discussionsupporting

confidence: 69%

PRKDC mutations in a SCID patient with profound neurological abnormalities

Woodbine¹,

Neal²,

Sasi³

et al. 2013

J. Clin. Invest.

133

134

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“…It is likely that accumulation of DSBs and/or DSB-induced de novo mutations in Pol␤-deficient cortex leads to cortical developmental disorders. Pol␤ polymorphisms have not been identified in the CNS, although several mutations in BER-related genes are identified to be associated with human brain dysfunction (Date et al, 2001;Takashima et al, 2002;Shen et al, 2010;Sobol, 2012;Hoch et al, 2017).…”

Section: The Impact Of Pol␤ Deficiency On Cortical Development and Fumentioning

confidence: 99%

Genome Stability by DNA Polymerase β in Neural Progenitors Contributes to Neuronal Differentiation in Cortical Development

et al. 2017

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DNA repair is crucial for genome stability in the developing cortex, as somatic de novo mutations cause neurological disorders. However, how DNA repair contributes to neuronal development is largely unknown. To address this issue, we studied the spatiotemporal roles of DNA polymerase ␤ (Pol␤), a key enzyme in DNA base excision repair pathway, in the developing cortex using distinct forebrain-specific conditional knock-out mice,

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“…In a similar manner to aprataxin and TDP1, loss of PNKP phosphatase activity results in delayed repair of cellular SSBs, and sensitivity to oxidative stress [109,136]. Patients with mutations in this protein suffer from microcephaly, early-onset seizures and developmental delay (MCSZ [137]). The spectrum of neurological symptoms in these patients could represent a very severe SSBR defect that is reminiscent of Xrcc1 Nes-Cre mice with an onset period in late development.…”

Section: Microcephaly With Early-onset Seizures and Developmental Delmentioning

confidence: 99%

DNA strand break repair and neurodegeneration

Rulten

Caldecott

2013

DNA Repair

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A number of DNA repair disorders are known to cause neurological problems. These disorders can be broadly characterised into early developmental, mid-to-late developmental or progressive. The exact developmental processes that are affected can influence disease pathology, with symptoms ranging from early embryonic lethality to late-onset ataxia. The category these diseases belong to depends on the frequency of lesions arising in the brain, the role of the defective repair pathway, and the nature of the mutation within the patient. Using observations from patients and transgenic mice, we discuss the importance of double strand break repair during neuroprogenitor proliferation and brain development and the repair of single stranded lesions in neuronal function and maintenance.

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Mutations in PNKP cause microcephaly, seizures and defects in DNA repair

Cited by 264 publications

References 27 publications

PRKDC mutations in a SCID patient with profound neurological abnormalities

PRKDC mutations in a SCID patient with profound neurological abnormalities

Genome Stability by DNA Polymerase β in Neural Progenitors Contributes to Neuronal Differentiation in Cortical Development

DNA strand break repair and neurodegeneration

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