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Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism.
Hum Genet 2014; 133(8):1023-39HG

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+Show Affiliations

Division of Genetic Medicine, Department of Pediatrics, Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington, Seattle, WA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24748105

Citation

Mirzaa, Ghayda M., et al. "Mutations in CENPE Define a Novel Kinetochore-centromeric Mechanism for Microcephalic Primordial Dwarfism." Human Genetics, vol. 133, no. 8, 2014, pp. 1023-39.
Mirzaa GM, Vitre B, Carpenter G, et al. Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. Hum Genet. 2014;133(8):1023-39.
Mirzaa, G. M., Vitre, B., Carpenter, G., Abramowicz, I., Gleeson, J. G., Paciorkowski, A. R., ... O'Driscoll, M. (2014). Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. Human Genetics, 133(8), pp. 1023-39. doi:10.1007/s00439-014-1443-3.
Mirzaa GM, et al. Mutations in CENPE Define a Novel Kinetochore-centromeric Mechanism for Microcephalic Primordial Dwarfism. Hum Genet. 2014;133(8):1023-39. PubMed PMID: 24748105.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. AU - Mirzaa,Ghayda M, AU - Vitre,Benjamin, AU - Carpenter,Gillian, AU - Abramowicz,Iga, AU - Gleeson,Joseph G, AU - Paciorkowski,Alex R, AU - Cleveland,Don W, AU - Dobyns,William B, AU - O'Driscoll,Mark, Y1 - 2014/04/20/ PY - 2013/05/20/received PY - 2014/03/31/accepted PY - 2014/4/22/entrez PY - 2014/4/22/pubmed PY - 2014/9/3/medline SP - 1023 EP - 39 JF - Human genetics JO - Hum. Genet. VL - 133 IS - 8 N2 - 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. SN - 1432-1203 UR - https://www.unboundmedicine.com/medline/citation/24748105/Mutations_in_CENPE_define_a_novel_kinetochore_centromeric_mechanism_for_microcephalic_primordial_dwarfism_ L2 - https://dx.doi.org/10.1007/s00439-014-1443-3 DB - PRIME DP - Unbound Medicine ER -