PNKP is required for maintaining the integrity of progenitor cell populations in adult mice

Shin, Wisoo; Alpaugh, Whitney; Hallihan, Laura J; Sinha, Sarthak; Crowther, Emilie; Martin, Gary R.; Scheidl-Yee, Teresa; Yang, Xiaoyan; Yoon, Grace; Goldsmith, Taylor; Berger, N. Daniel; Almeida, Luiz Gn de; Dufour, Antoine; Dobrinski, Ina; Weinfeld, Michael; Jirik, Frank R.; Biernaskie, Jeff

doi:10.26508/lsa.202000790

Cited by 5 publications

(3 citation statements)

References 68 publications

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“…We expand the phenotype of PNKP variants with lissencephaly, which has not been previously reported to our knowledge. It was found that PNKP knockout mice had significantly reduced doublecortin +ve (DCX+ve) neuroblasts in the dorsolateral horn, with PNKP deficiency disrupting neural stem cell maintenance 43 . Doublecortin (encoded by DCX gene) interacts with platelet‐activating factor acetylhydrolase (encoded by LIS1 gene), and both are essential to maintain microtubule function for neuronal migration in the developing cerebral cortex 44 which may explain the lissencephaly phenotype.…”

Section: Discussionmentioning

confidence: 99%

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

Elkhateeb,

Issa,

Elbendary

et al. 2024

Clinical Genetics

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Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early‐onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10‐year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic–clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype–genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.

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Section: Discussionmentioning

confidence: 99%

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

Elkhateeb,

Issa,

Elbendary

et al. 2024

Clinical Genetics

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“…Moreover, loss of Pnkp proved to be more severe when compared to Lig4 or Xrcc1 loss, indicating that at least in mice, Pnkp may be involved in the repair of a wider range of lesions, demonstrating an important difference between PNKP function in human and mouse ( Shimada et al, 2015 ). In general, Pnkp loss has been shown to induce a thinning in the cerebral cortex, abundant p53-dependent apoptosis and impaired NPCs proliferation, leading to microcephaly ( Shimada et al, 2015 ; Shin et al, 2021 ).…”

Section: Microcephaly Associated With Dna Damagementioning

confidence: 99%

DNA damage and repair: underlying mechanisms leading to microcephaly

Ribeiro,

Altinisik,

Rajan

et al. 2023

Front. Cell Dev. Biol.

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DNA-damaging agents and endogenous DNA damage constantly harm genome integrity. Under genotoxic stress conditions, the DNA damage response (DDR) machinery is crucial in repairing lesions and preventing mutations in the basic structure of the DNA. Different repair pathways are implicated in the resolution of such lesions. For instance, the non-homologous DNA end joining and homologous recombination pathways are central cellular mechanisms by which eukaryotic cells maintain genome integrity. However, defects in these pathways are often associated with neurological disorders, indicating the pivotal role of DDR in normal brain development. Moreover, the brain is the most sensitive organ affected by DNA-damaging agents compared to other tissues during the prenatal period. The accumulation of lesions is believed to induce cell death, reduce proliferation and premature differentiation of neural stem and progenitor cells, and reduce brain size (microcephaly). Microcephaly is mainly caused by genetic mutations, especially genes encoding proteins involved in centrosomes and DNA repair pathways. However, it can also be induced by exposure to ionizing radiation and intrauterine infections such as the Zika virus. This review explains mammalian cortical development and the major DNA repair pathways that may lead to microcephaly when impaired. Next, we discuss the mechanisms and possible exposures leading to DNA damage and p53 hyperactivation culminating in microcephaly.

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“…Moreover, in the PNKP KO mice adult is strongly impaired in neurogenesis and subventricular zones (SVZ) cell population. Especially, PNKP deletion affects a rapid inhibition of cell proliferation and self-renewal in neural progenitor cells (Shin et al 2021).…”

Section: Detection Of Novel Genes On Recessive Heterozygous Alleles I...mentioning

confidence: 99%

Detection of Novel Genes on Recessive Heterozygous Alleles in Pig Breeding: A Review

Tran

Linh

et al. 2022

IJAR

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In this paper, we illustrated several examples of overdominance phenomenon in pigs, in which the selection in favor of lethal genes that generates production traits such as body weight, body condition score and milk yield. We searched the database and literatures on NCBI Databases, Google scholar, Google Web tools. Five novel candidates of Bardet-Biedl Syndrome 9 (BBS9) gene, Transcriptional Adapter-Ada2 (TADA2) gene, RNA Polymerase I subunit B (POLR1B), Ribosome biogenesis homolog (URB1), Polynucleotide kinase 3’-phosphatase (PNKP) are reported to positively affect food intake, cell proliferation. However, embryonic and developmental lethality are displayed in the homozygous recessive individuals. The objective of this review is to show the relationship between genotypes, phenotypes and functions of these novel genes which could benefit pig breeding industry.

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PNKP is required for maintaining the integrity of progenitor cell populations in adult mice

Cited by 5 publications

References 68 publications

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

DNA damage and repair: underlying mechanisms leading to microcephaly

Detection of Novel Genes on Recessive Heterozygous Alleles in Pig Breeding: A Review

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