title: Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism.
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.
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington, Seattle, WA, USA.
authors.forename: Ghayda M
authors.initials: GM
authors.lastname: Mirzaa
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vitre
authors.forename: Gillian
authors.initials: G
authors.lastname: Carpenter
authors.forename: Iga
authors.initials: I
authors.lastname: Abramowicz
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.forename: Alex R
authors.initials: AR
authors.lastname: Paciorkowski
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002453:Cell Cycle; D002478:Cells, Cultured; D002503:Centromere / Q000502:physiology*; D018385:Centrosome / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D020090:Chromosome Segregation; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology; D004392:Dwarfism / Q000235:genetics*; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D006801:Humans; D018386:Kinetochores / Q000502:physiology*; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008938:Mitosis / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C068688:centromere protein E; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases
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