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PLoS One. 2017 Dec 11;12(12):e0189324. doi: 10.1371/journal.pone.0189324. eCollection 2017.

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

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Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, United States of America.
Harvard Medical School, Boston, Massachusetts, United States of America.
Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
Department of Biology, University of Miami, Coral Gables, Florida, United States of America.
Department of Dermatology, EB House Austria, University Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria.
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.


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.

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