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Disturbed chromosome segregation and multipolar spindle formation in a patient with CHAMP1 mutation.

ABSTRACT: BACKGROUND:Patients with intellectual disability (ID) typically exhibit significant defects in both intelligence and adaptive behavior. Aberration of several genes involved in proper progression of mitosis has been reported to underlie ID. Here, we report a new patient with a novel mutation of CHAMP1. METHODS:Whole exome sequencing (WES) analysis was performed. We isolated lymphoblast cells from the CHAMP1 patient and observed chromosome segregation. RESULTS:We identified a de novo frameshift mutation in CHAMP1. We find that these cells exhibit an increase in centrosome number and resulting multipolar spindle formation. The phenotypes observed in the patient's lymphoblastoid cells were presumably because of cytokinesis failure. We also confirm the identical phenotypes in human culture cells depleted of CHAMP1. CONCLUSION:CHAMP1 encodes a protein regulating kinetochore-microtubule attachment and chromosome segregation. These data strongly support that CHAMP1 mutations cause ID, and suggest that CHAMP1 is critical for progression of cytokinesis and maintenance of centrosome number.

SUBMITTER: Okamoto N

PROVIDER: S-EPMC5606869 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Disturbed chromosome segregation and multipolar spindle formation in a patient with <i>CHAMP1</i> mutation.

Okamoto Nobuhiko N Tsuchiya Yuki Y Kuki Ichiro I Yamamoto Toshiyuki T Saitsu Hirotomo H Kitagawa Daiju D Matsumoto Naomichi N

Molecular genetics & genomic medicine 20170712 5

<h4>Background</h4>Patients with intellectual disability (ID) typically exhibit significant defects in both intelligence and adaptive behavior. Aberration of several genes involved in proper progression of mitosis has been reported to underlie ID. Here, we report a new patient with a novel mutation of <i>CHAMP1</i>.<h4>Methods</h4>Whole exome sequencing (WES) analysis was performed. We isolated lymphoblast cells from the <i>CHAMP1</i> patient and observed chromosome segregation.<h4>Results</h4>W ...[more]

PMID: 28944241

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Project description:BackgroundNormal cell division is coordinated by a bipolar mitotic spindle, ensuring symmetrical segregation of chromosomes. Cancer cells, however, occasionally divide into three or more directions. Such multipolar mitoses have been proposed to generate genetic diversity and thereby contribute to clonal evolution. However, this notion has been little validated experimentally.Principal findingsChromosome segregation and DNA content in daughter cells from multipolar mitoses were assessed by multiphoton cross sectioning and fluorescence in situ hybridization in cancer cells and non-neoplastic transformed cells. The DNA distribution resulting from multipolar cell division was found to be highly variable, with frequent nullisomies in the daughter cells. Time-lapse imaging of H2B/GFP-labelled multipolar mitoses revealed that the time from the initiation of metaphase to the beginning of anaphase was prolonged and that the metaphase plates often switched polarity several times before metaphase-anaphase transition. The multipolar metaphase-anaphase transition was accompanied by a normal reduction of cellular cyclin B levels, but typically occurred before completion of the normal separase activity cycle. Centromeric AURKB and MAD2 foci were observed frequently to remain on the centromeres of multipolar ana-telophase chromosomes, indicating that multipolar mitoses were able to circumvent the spindle assembly checkpoint with some sister chromatids remaining unseparated after anaphase. Accordingly, scoring the distribution of individual chromosomes in multipolar daughter nuclei revealed a high frequency of nondisjunction events, resulting in a near-binomial allotment of sister chromatids to the daughter cells.ConclusionThe capability of multipolar mitoses to circumvent the spindle assembly checkpoint system typically results in a near-random distribution of chromosomes to daughter cells. Spindle multipolarity could thus be a highly efficient generator of genetically diverse minority clones in transformed cell populations.

Dataset Information

Disturbed chromosome segregation and multipolar spindle formation in a patient with CHAMP1 mutation.

Publications

Disturbed chromosome segregation and multipolar spindle formation in a patient with <i>CHAMP1</i> mutation.

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