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https://hdl.handle.net/11499/8909
Title: | Analysis of centrosome and DNA damage response in PLK4 associated Seckel syndrome | Authors: | Dinçer, T. Yorgancıoğlu-Budak, G. Ölmez, A. Er, İ. Dodurga, Yavuz Özdemir, Özmert M.A. Toraman, B. |
Keywords: | centrin centrin 1 DNA gamma tubulin messenger RNA polo like kinase 4 unclassified drug PLK4 protein, human protein serine threonine kinase adult apoptosis Article cell cycle G2 phase cell cycle progression cellular distribution centriole child chromosome 4q clinical article consanguineous marriage controlled study DNA damage response female gene mapping genetic association genome-wide association study genomic instability genotype homozygosity human human cell human tissue infant male metaphase mitosis preschool child priority journal real time polymerase chain reaction RNA splice site school child Seckel syndrome single nucleotide polymorphism sister chromatid exchange skin fibroblast translation termination Turk (people) young adult case report cell culture centrosome chromosome 4 cytology DNA damage dwarfism fibroblast genetics metabolism microcephaly mutation pathology pedigree RNA splicing Adult Cells, Cultured Centrosome Child Child, Preschool Chromosomes, Human, Pair 4 DNA Damage Dwarfism Female Fibroblasts Genomic Instability Humans Infant Male Microcephaly Mitosis Mutation Pedigree Protein-Serine-Threonine Kinases RNA Splicing |
Publisher: | Nature Publishing Group | Abstract: | Microcephalic primordial dwarfism (MPD) is a group of autosomal recessive inherited single-gene disorders with intrauterine and postnatal global growth failure. Seckel syndrome is the most common form of the MPD. Ten genes are known with Seckel syndrome. Using genome-wide SNP genotyping and homozygosity mapping we mapped a Seckel syndrome gene to chromosomal region 4q28.1-q28.3 in a Turkish family. Direct sequencing of PLK4 (polo-like kinase 4) revealed a homozygous splicing acceptor site transition (c.31-3 A>G) that results in a premature translation termination (p.[=,Asp11Profs*14]) causing deletion of all known functional domains of the protein. PLK4 is a master regulator of centriole biogenesis and its deficiency has recently been associated with Seckel syndrome. However, the role of PLK4 in genomic stability and the DNA damage response is unclear. Evaluation of the PLK4-Seckel fibroblasts obtained from patient revealed the expected impaired centriole biogenesis, disrupted mitotic morphology, G 2 /M delay, and extended cell doubling time. Analysis of the PLK4-Seckel cells indicated that PLK4 is also essential for genomic stability and DNA damage response. These findings provide mechanistic insight into the pathogenesis of the severe growth failure associated with PLK4-deficiency. © 2017 European Society of Human Genetics All rights reserved. | URI: | https://hdl.handle.net/11499/8909 https://doi.org/10.1038/ejhg.2017.120 |
ISSN: | 1018-4813 |
Appears in Collections: | PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection Tıp Fakültesi Koleksiyonu WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection |
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