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Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism

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Abstract

Defects in centrosome, centrosomal-associated and spindle-associated proteins are the most frequent cause of primary microcephaly (PM) and microcephalic primordial dwarfism (MPD) syndromes in humans. Mitotic progression and segregation defects, microtubule spindle abnormalities and impaired DNA damage-induced G2-M cell cycle checkpoint proficiency have been documented in cell lines from these patients. This suggests that impaired mitotic entry, progression and exit strongly contribute to PM and MPD. Considering the vast protein networks involved in coordinating this cell cycle stage, the list of potential target genes that could underlie novel developmental disorders is large. One such complex network, with a direct microtubule-mediated physical connection to the centrosome, is the kinetochore. This centromeric-associated structure nucleates microtubule attachments onto mitotic chromosomes. Here, we described novel compound heterozygous variants in CENPE in two siblings who exhibit a profound MPD associated with developmental delay, simplified gyri and other isolated abnormalities. CENPE encodes centromere-associated protein E (CENP-E), a core kinetochore component functioning to mediate chromosome congression initially of misaligned chromosomes and in subsequent spindle microtubule capture during mitosis. Firstly, we present a comprehensive clinical description of these patients. Then, using patient cells we document abnormalities in spindle microtubule organization, mitotic progression and segregation, before modeling the cellular pathogenicity of these variants in an independent cell system. Our cellular analysis shows that a pathogenic defect in CENP-E, a kinetochore-core protein, largely phenocopies PCNT-mutated microcephalic osteodysplastic primordial dwarfism-type II patient cells. PCNT encodes a centrosome-associated protein. These results highlight a common underlying pathomechanism. Our findings provide the first evidence for a kinetochore-based route to MPD in humans.

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Acknowledgments

We wish to thank the family and the referring physicians for their contribution to this study. The O’Driscoll laboratory is funded by Cancer Research UK, Leukaemia Lymphoma Research (UK) and the Medical Research Council (UK). The Dobyns laboratory is funded by the US National Institutes of Health under NINDS grant NS058721. The Paciorkowski laboratory is funded by the US National Institutes of Health under NINDS grant NS078054. Thanks also to the Center for Integrated Research Computing at the University of Rochester Medical Center for the computational resources for data analysis. The Cleveland laboratory is supported by the Ludwig Cancer Institute and NIH (R01-GM29513). B.V is a Human Frontiers Science Program postdoctoral fellow.

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The authors declare they have no conflict of interest.

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Authors and Affiliations

  1. Division of Genetic Medicine, Department of Pediatrics, Center for Integrative Brain Research, Seattle Children’s Research Institute, University of Washington, Seattle, WA, USA

    Ghayda M. Mirzaa & William B. Dobyns

  2. Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA

    Benjamin Vitre & Don W. Cleveland

  3. Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, BN1 9RQ, UK

    Gillian Carpenter, Iga Abramowicz & Mark O’Driscoll

  4. Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, CA, USA

    Joseph G. Gleeson

  5. Department of Neurology, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA

    Alex R. Paciorkowski

  6. Department of Pediatrics, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA

    Alex R. Paciorkowski

  7. Department of Biomedical Genetics, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA

    Alex R. Paciorkowski

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  1. Ghayda M. Mirzaa
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  2. Benjamin Vitre
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  7. Don W. Cleveland
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Correspondence to Mark O’Driscoll.

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Mirzaa, G.M., Vitre, B., Carpenter, G. et al. Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. Hum Genet 133, 1023–1039 (2014). https://doi.org/10.1007/s00439-014-1443-3

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  • DOI: https://doi.org/10.1007/s00439-014-1443-3

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