The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort

Garrelfs, Mark R.; Takada, Shinako; Kamsteeg, Erik‐Jan; Pegge, Sjoert; Mancini, Grazia M.S.; Engelen, Marc; Warrenburg, Bart van de; Rennings, Alexander J.; Gaalen, Judith van; Peters, Ivo; Weemaes, C.M.R.; Burg, Mirjam van der; Willemsen, M.A.A.P.

doi:10.1016/j.pediatrneurol.2020.07.014

Cited by 8 publications

(6 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutation sites of PNKP have been found in all three domains-FHA, phosphatase and kinase-in these cases of MCSZ 5,[8][9][10][11][12]21 . One patient with AOA4 was diagnosed with cerebellar pilocytic astrocytoma at the age of 23 years 22 , and a second AOA4 patient developed a cerebellar hemangioblastoma resulting from a concurrent mutation in the von Hippel-Lindau gene 23 , but until now no cancer has been reported in an MCSZ patient.…”

mentioning

confidence: 99%

Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor

Jiang

Murray

Cole

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3′-phosphatase and DNA 5′-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. Functional and biochemical studies demonstrated these PNKP mutations significantly diminished DNA kinase/phosphatase activities, altered its cellular distribution, caused defective repair of DNA single/double stranded breaks, and were associated with a higher propensity for oncogenic transformation. Our findings indicate that specific PNKP mutations may contribute to tumor initiation within susceptible cells in the CNS by limiting DNA damage repair and increasing rates of spontaneous mutations resulting in pediatric glioma associated driver mutations such as ATRX and TP53.

show abstract

mentioning

confidence: 99%

Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor

Jiang

Murray

Cole

et al. 2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Smaller introns are associated with a higher likelihood of intron retention (35), a mechanism we proved for two novel variants here. RNA analyses of disease-associated PNKP variants were previously not reported, despite many intronic and splice sites affecting changes described (6,26,28,29,(36)(37)(38)(39)(40)(41)(42)(43). The results of our RNA splicing analyses for one novel silent variant, one known splice donor variant and moreover one variant annotated as missense point toward a likely underappreciated pathomechanism.…”

Section: Discussionmentioning

confidence: 62%

Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain

Neuser

Krey

Schwan³

et al. 2021

Preprint

View full text Add to dashboard Cite

Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Detailed pathological examination of a male fetus revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities in a sibling fetus. Prenatal trio exome sequencing identified compound-heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sibling fetus. Through RNA analyses, we characterized skipping of exon 4 affecting the PNKP Forkhead-associated (FHA) and Phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the same splice-donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro) and c.151G>C, p.(Val51Leu), respectively). RNA-seq showed complex splicing events for c.1029+2T>C and c.151G>C. Computational modelling and structural analysis revealed significant clustering of missense variants in the FHA domain, with some variants potentially generating structural damage. Our detailed clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modelling, we highlight the mutational complexity and exemplify a framework for variant characterization in this multi-domain protein.

show abstract

“…The association of a single gene with distinct phenotypes such as NDDs and CMT2 may be surprising but is not without precedence. The allelic series of PNKP , a gene encoding another SSB/DSB repair enzyme, polynucleotide kinase 3-prime phosphatase, is relevant as it ranges from Charcot-Marie-Tooth disease, type 2B2 [MIM: 605589] to ataxia-oculomotor apraxia 4 [MIM: 616267] and microcephaly, seizures, and developmental delay [MIM: 613402] 72 . Other examples include SURF1 (CMT type 4K [MIM: 616684]; mitochondrial complex IV deficiency, MIM: 220110), YARS1 (CMT, dominant intermediate C [MIM: 608323]; infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2 [MIM: 619418]), ATP1A1 (CMT, axonal, type 2DD [MIM: 618036]; hypomagnesemia, seizures, and mental retardation 2 [MIM: 618314]), MORC2 (CMT, axonal, type 2Z [MIM: 616688]; developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy [MIM: 619090]), and AIFM1 (combined oxidative phosphorylation deficiency 6 [MIM: 300816]; Cowchock syndrome [MIM: 310490]).…”

Section: Discussionmentioning

confidence: 99%

Monoallelic variation inDHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease

Calame

Guo

Wang

et al. 2023

Preprint

View full text Add to dashboard Cite

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer.DHX9encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains without disease trait associations. Using exome sequencing and family-based rare variant analysis, we identified 20 individuals withde novo, ultra-rare, heterozygous missense or loss-of-function (LoF)DHX9variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative HPO analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigatedDHX9variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from a patient with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.(Gly411Glu) and p.(Arg761Gln), altered DHX9 ATPase activity. The severe NDD-associated variant p.(Arg141Gln) did not impact DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks.Dhx9-/-mice exhibit hypoactivity in novel environments, tremor, and sensorineural hearing loss. Taken together, these results establishDHX9as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.

show abstract

The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort

Cited by 8 publications

References 37 publications

Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor

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 in the FHA and Phosphatase domain

Monoallelic variation inDHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease

Contact Info

Product

Resources

About