PUBLICATION

Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype

Authors
Yao, L., Chen, J., Wu, X., Jia, S., Meng, A.
ID
ZDB-PUB-171007-1
Date
2017
Source
Human molecular genetics   26(21): 4168-4180 (Journal)
Registered Authors
Chen, Jing, Meng, Anming
Keywords
none
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Cell Cycle Proteins/genetics*
  • Cell Cycle Proteins/metabolism
  • Congenital Microtia/genetics*
  • DNA Replication
  • Disease Models, Animal
  • Female
  • Growth Disorders/genetics*
  • Loss of Function Mutation/genetics
  • Male
  • Micrognathism/genetics*
  • Nuclear Proteins/genetics*
  • Nuclear Proteins/metabolism
  • Patella/abnormalities*
  • Phenotype
  • Replication Origin
  • Zebrafish/metabolism
(all 19)
PubMed
28985365 Full text @ Hum. Mol. Genet.
Abstract
Cell Division Cycle 6 (Cdc6) is a component of pre-replicative complex (preRC) forming on DNA replication origins in eukaryotes. Recessive mutations in ORC1, ORC4, ORC6, CDT1 or CDC6 of the preRC in human cause Meier-Gorlin syndrome (MGS) that is characterized by impaired post-natal growth, short stature and microcephaly. However, vertebrate models of MGS have not been reported. Through N-ethyl-N-nitrosourea mutagenesis and Cas9 knockout, we generate several cdc6 mutant lines in zebrafish. Loss-of-function mutations of cdc6, as manifested by cdc6tsu4305 and cdc6tsu7cd mutants, lead to embryonic lethality due to cell cycle arrest at the S phase and extensive apoptosis. Embryos homozygous for a cdc6 hypomorphic mutation, cdc6tsu21cd, develop normally during embryogenesis. Later on, compared with their wild-type (WT) siblings, cdc6tsu21cd mutant fish show growth retardation, and their body weight and length in adulthood are greatly reduced, which resemble human MGS. Surprisingly, cdc6tsu21cd mutant fish become males with a short life and fail to mate with WT females, suggesting defective reproduction. Overexpression of Cdc6 mutant forms, which mimic human CDC6(T323R) mutation found in a MGS patient, in zebrafish cdc6tsu4305 mutant embryos partially represses cell death phenotype, suggesting that the human CDC6(T323R) mutation is a hypomorph. cdc6tsu21cd mutant fish will be useful to detect more tissue defects and develop medical treatment strategies for MGS patients.
Genes / Markers
Marker Marker Type Name
aspmGENEassembly factor for spindle microtubules
bbc3GENEBCL2 binding component 3
cdc6GENEcell division cycle 6 homolog (S. cerevisiae)
cdk1GENEcyclin dependent kinase 1
cdk2GENEcyclin dependent kinase 2
cenpfGENEcentromere protein F
stag1aGENESTAG1 cohesin complex component a
tp53GENEtumor protein p53
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Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
tsu7cd
    Complex
    tsu21cd
      Indel
      tsu4305
        Point Mutation
        1 - 3 of 3
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        Human Disease / Model
        Human Disease Fish Conditions Evidence
        Meier-Gorlin syndromecdc6tsu21cd/tsu21cdstandard conditionsTAS
        1 - 1 of 1
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        Sequence Targeting Reagents
        Target Reagent Reagent Type
        cdc6CRISPR1-cdc6CRISPR
        cdc6MO1-cdc6MRPHLNO
        cdc6MO2-cdc6MRPHLNO
        1 - 3 of 3
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        Fish
        Antibodies
        Orthology
        Engineered Foreign Genes
        No data available
        Mapping