PUBLICATION

A defect in the inner kinetochore protein CENPT causes a new syndrome of severe growth failure

Authors
Hung, C.Y., Volkmar, B., Baker, J.D., Bauer, J.W., Gussoni, E., Hainzl, S., Klausegger, A., Lorenzo, J., Mihalek, I., Rittinger, O., Tekin, M., Dallman, J.E., Bodamer, O.A.
ID
ZDB-PUB-171212-11
Date
2017
Source
PLoS One   12: e0189324 (Journal)
Registered Authors
Dallman, Julia
Keywords
none
MeSH Terms
  • Zebrafish/genetics
  • Growth Disorders/genetics*
  • Models, Animal
  • Chromosomal Proteins, Non-Histone/genetics*
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Female
  • Animals
(all 9)
PubMed
29228025 Full text @ PLoS One
Abstract
Primordial growth failure has been linked to defects in the biology of cell division and replication. The complex processes involved in microtubule spindle formation, organization and function have emerged as a dominant patho-mechanism in these conditions. The majority of reported disease genes encode for centrosome and centriole proteins, leaving kinetochore proteins by which the spindle apparatus interacts with the chromosomes largely unaccounted for. We report a novel disease gene encoding the constitutive inner kinetochore member CENPT, which is involved in kinetochore targeting and assembly, resulting in severe growth failure in two siblings of a consanguineous family. We herein present studies on the molecular and cellular mechanisms that explain how genetic mutations in this gene lead to primordial growth failure. In both, affected human cell lines and a zebrafish knock-down model of Cenpt, we observed aberrations in cell division with abnormal accumulation of micronuclei and of nuclei with increased DNA content arising from incomplete and/or irregular chromosomal segregation. Our studies underscore the critical importance of kinetochore function for overall body growth and provide new insight into the cellular mechanisms implicated in the spectrum of these severe growth disorders.
Genes / Markers
Figures
Figure Gallery (1 images)
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Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO1-cenptstandard conditionsPrim-5
WT + MO2-cenptstandard conditionsPrim-5
WT + MO2-cenptstandard conditionsPrim-5
WT + MO3-cenptstandard conditionsPrim-5
WT + MO3-cenptstandard conditionsPrim-5
WT + MO3-cenptstandard conditionsLong-pec
WT + MO3-cenptstandard conditionsLong-pec
kca66Tg; kca6Tg + MO3-cenptstandard conditions1-cell to Dome
kca66Tg; kca6Tg + MO3-cenptstandard conditions1-cell to Dome
1 - 9 of 9
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
kca6TgTransgenic Insertion
    kca66TgTransgenic Insertion
      1 - 2 of 2
      Show
      Human Disease / Model
      Human Disease Fish Conditions Evidence
      Seckel syndromeWT + MO3-cenptstandard conditionsTAS
      1 - 1 of 1
      Show
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      cenptMO2-cenptMRPHLNO
      cenptMO1-cenptMRPHLNO
      cenptMO3-cenptMRPHLNO
      1 - 3 of 3
      Show
      Fish
      Fish
      kca66Tg; kca6Tg
      kca66Tg; kca6Tg + MO3-cenpt
      WT + MO1-cenpt
      WT + MO2-cenpt
      WT + MO3-cenpt
      1 - 5 of 5
      Show
      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      GFPEFGGFP
      1 - 1 of 1
      Show
      Mapping
      No data available
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      Citation
      Hung, C.Y., Volkmar, B., Baker, J.D., Bauer, J.W., Gussoni, E., Hainzl, S., Klausegger, A., Lorenzo, J., Mihalek, I., Rittinger, O., Tekin, M., Dallman, J.E., Bodamer, O.A. (2017) A defect in the inner kinetochore protein CENPT causes a new syndrome of severe growth failure. PLoS One. 12:e0189324.