Please use this identifier to cite or link to this item: 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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