Kinetochore KMN network gene CASC5 mutated in primary microcephaly.

[en] Several genes expressed at the centrosome or spindle pole have been reported to underlie autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder consisting of an important brain size reduction present since birth, associated with mild-to-moderate mental handicap and no other neurological feature nor associated malformation. Here, we report a mutation of CASC5 (aka Blinkin, or KNL1, or hSPC105) in MCPH patients from three consanguineous families, in one of which we initially reported the MCPH4 locus. The combined logarithm of odds score of the three families was >6. All patients shared a very rare homozygous mutation of CASC5. The mutation induced skipping of exon 18 with subsequent frameshift and truncation of the predicted protein. CASC5 is part of the KMN network of the kinetochore and is required for proper microtubule attachment to the chromosome centromere and for spindle-assembly checkpoint (SAC) activation during mitosis. Like MCPH gene ASPM, CASC5 is upregulated in the ventricular zone (VZ) of the human fetal brain. CASC5 binds BUB1, BUBR1, ZWINT-1 and interestingly it binds to MIS12 through a protein domain which is truncated by the mutation. CASC5 localized at the equatorial plate like ZWINT-1 and BUBR1, while ASPM, CEP152 and PCTN localized at the spindle poles in our patients and in controls. Comparison of primate and rodent lineages indicates accelerated evolution of CASC5 in the human lineage. Our data provide strong evidence for CASC5 as a novel MCPH gene, and underscore the role of kinetochore integrity in proper volumetric development of the human brain.

Disciplines :

Genetics & genetic processes

Author, co-author :

Genin, Anne

Desir, Julie

Lambert, Nelle

Biervliet, Martine

Van Der Aa, Nathalie

PIERQUIN, Geneviève ; Centre Hospitalier Universitaire de Liège - CHU > Génétique

Killian, Audrey

Tosi, Mario

Urbina, Montse

Lefort, Anne

More authors (3 more)

Language :

English

Title :

Kinetochore KMN network gene CASC5 mutated in primary microcephaly.

Publication date :

2012

Journal title :

Human Molecular Genetics

ISSN :

0964-6906

eISSN :

1460-2083

Publisher :

Oxford University Press, United Kingdom

Volume :

Issue :

Pages :

5306-17

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 07 May 2013

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Bibliography

Barkovich, A.J., Guerrini, R., Kuzniecky, R.I., Jackson, G.D. and Dobyns, W.B. (2012) A developmental and genetic classification for malformations of cortical development: update 2012. Brain, 135, 1348-1369.
Bond, J., Roberts, E., Mochida, G.H., Hampshire, D.J., Scott, S., Askham, J.M., Springell, K., Mahadevan, M., Crow, Y.J., Markham, A.F. et al. (2002) ASPM is a major determinant of cerebral cortical size. Nat. Genet., 32, 316-320.
Tolmie, J.L., McNay, M., Stephenson, J.B., Doyle, D. and Connor, J.M. (1987) Microcephaly: genetic counselling and antenatal diagnosis after the birth of an affected child. Am. J. Med. Genet., 27, 583-594.
Woods, C.G., Bond, J. and Enard, W. (2005) Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am. J. Hum. Genet., 76, 717-728.
Jackson, A.P., Eastwood, H., Bell, S.M., Adu, J., Toomes, C., Carr, I.M., Roberts, E., Hampshire, D.J., Crow, Y.J., Mighell, A.J. et al. (2002) Identification of microcephalin, a protein implicated in determining the size of the human brain. Am. J. Hum. Genet., 71, 136-142.
Nicholas, A.K., Khurshid, M., Desir, J., Carvalho, O.P., Cox, J.J., Thornton, G., Kausar, R., Ansar, M., Ahmad, W., Verloes, A. et al. (2010) WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat. Genet., 42, 1010-1014.
Bond, J., Roberts, E., Springell, K., Lizarraga, S.B., Scott, S., Higgins, J., Hampshire, D.J., Morrison, E.E., Leal, G.F., Silva, E.O. et al. (2005) A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat. Genet., 37, 353-355.
Guernsey, D.L., Jiang, H., Hussin, J., Arnold, M., Bouyakdan, K., Perry, S., Babineau-Sturk, T., Beis, J., Dumas, N., Evans, S.C. et al. (2010) Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am. J. Hum. Genet., 87, 40-51.
Kumar, A., Girimaji, S.C., Duvvari, M.R. and Blanton, S.H. (2009) Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. Am. J. Hum. Genet., 84, 286-290.
Sir, J.H., Barr, A.R., Nicholas, A.K., Carvalho, O.P., Khurshid, M., Sossick, A., Reichelt, S., D'Santos, C., Woods, C.G. and Gergely, F. (2011) A primary microcephaly protein complex forms a ring around parental centrioles. Nat. Genet., 43, 1147-1153.
Hussain, M.S., Baig, S.M., Neumann, S., Nurnberg, G., Farooq, M., Ahmad, I., Alef, T., Hennies, H.C., Technau, M., Altmuller, J. et al. (2012) A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function. Am. J. Hum. Genet., 90, 871-878.
Marchal, J.A., Ghani, M., Schindler, D., Gavvovidis, I., Winkler, T., Esquitino, V., Sternberg, N., Busche, A., Krawitz, P., Hecht, J. et al. (2011) Misregulation of mitotic chromosome segregation in a new type of autosomal recessive primary microcephaly. Cell Cycle, 10, 2967-2977.
Zhong, X., Liu, L., Zhao, A., Pfeifer, G.P. and Xu, X. (2005) The abnormal spindle-like, microcephaly-associated (ASPM) gene encodes a centrosomal protein. Cell Cycle, 4, 1227-1229.
Zhong, X., Pfeifer, G.P. and Xu, X. (2006) Microcephalin encodes a centrosomal protein. Cell Cycle, 5, 457-458.
Fish, J.L., Kosodo, Y., Enard, W., Paabo, S. and Huttner, W.B. (2006) Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells. Proc. Natl Acad. Sci. USA, 103, 10438-10443.
Gruber, R., Zhou, Z., Sukchev, M., Joerss, T., Frappart, P.O. and Wang, Z.Q. (2011) MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway. Nat. Cell Biol., 13, 1325-1334.
Peng, G., Yim, E.K., Dai, H., Jackson, A.P., Burgt, I., Pan, M.R., Hu, R., Li, K. and Lin, S.Y. (2009) BRIT1/MCPH1 links chromatin remodelling to DNA damage response. Nat. Cell Biol., 11, 865-872.
Jamieson, C.R., Govaerts, C. and Abramowicz, M.J. (1999) Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. Am. J. Hum. Genet., 65, 1465-1469.
Kiyomitsu, T., Obuse, C. and Yanagida, M. (2007) Human Blinkin/ AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1. Dev. Cell, 13, 663-676.
Kline, S.L., Cheeseman, I.M., Hori, T., Fukagawa, T. and Desai, A. (2006) The human Mis12 complex is required for kinetochore assembly and proper chromosome segregation. J. Cell Biol., 173, 9-17.
Krivega, I. and Dean, A. (2011) Enhancer and promoter interactions-long distance calls. Curr. Opin. Genet. Dev., 22, 79-85.
Volkmann, B.A., Zinkevich, N.S., Mustonen, A., Schilter, K.F., Bosenko, D.V., Reis, L.M., Broeckel, U., Link, B.A. and Semina, E.V. (2011) Potential novel mechanism for Axenfeld-Rieger syndrome: deletion of a distant region containing regulatory elements of PITX2. Invest. Ophthalmol. Vis. Sci., 52, 1450-1459.
Halligan, D.L., Oliver, F., Guthrie, J., Stemshorn, K.C., Harr, B. and Keightley, P.D. (2011) Positive and negative selection in murine ultraconserved noncoding elements. Mol. Biol. Evol., 28, 2651-2660.
Bejerano, G., Pheasant, M., Makunin, I., Stephen, S., Kent, W.J., Mattick, J.S. and Haussler, D. (2004) Ultraconserved elements in the human genome. Science, 304, 1321-1325.
Fietz, S.A., Lachmann, R., Brandl, H., Kircher, M., Samusik, N., Schroder, R., Lakshmanaperumal, N., Henry, I., Vogt, J., Riehn, A. et al. (2012) Transcriptomes of germinal zones of human and mouse fetal neocortex suggest a role of extracellular matrix in progenitor self-renewal. Proc. Natl Acad. Sci. USA, 109, 11836-11841.
Cheeseman, I.M., Hori, T., Fukagawa, T. and Desai, A. (2008) KNL1 and the CENP-H/I/K complex coordinately direct kinetochore assembly in vertebrates. Mol. Biol. Cell, 19, 587-594.
Lampson, M.A. and Kapoor, T.M. (2005) The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments. Nat. Cell Biol., 7, 93-98.
Liu, D., Vleugel, M., Backer, C.B., Hori, T., Fukagawa, T., Cheeseman, I.M. and Lampson, M.A. (2010) Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase. J. Cell Biol., 188, 809-820.
Welburn, J.P., Vleugel, M., Liu, D., Yates, J.R. III, Lampson, M.A., Fukagawa, T. and Cheeseman, I.M. (2010) Aurora B phosphorylates spatially distinct targets to differentially regulate the kinetochore-microtubule interface. Mol. Cell, 38, 383-392.
Shepperd, L.A., Meadows, J.C., Sochaj, A.M., Lancaster, T.C., Zou, J., Buttrick, G.J., Rappsilber, J., Hardwick, K.G. and Millar, J.B. (2012) Phosphodependent recruitment of Bub1 and Bub3 to Spc7/KNL1 by Mph1 kinase maintains the spindle checkpoint. Curr. Biol., 22, 891-899.
Kang, H.J., Kawasawa, Y.I., Cheng, F., Zhu, Y., Xu, X., Li, M., Sousa, A.M., Pletikos, M., Meyer, K.A., Sedmak, G. et al. (2011) Spatio-temporal transcriptome of the human brain. Nature, 478, 483-489.
Kim, D.S. and Hahn, Y. (2011) Identification of novel phosphorylation modification sites in human proteins that originated after the human- chimpanzee divergence. Bioinformatics, 27, 2494-2501.
Kiyomitsu, T., Murakami, H. and Yanagida, M. (2011) Protein interaction domain mapping of human kinetochore protein Blinkin reveals a consensus motif for binding of spindle assembly checkpoint proteins Bub1 and BubR1. Mol. Cell Biol., 31, 998-1011.
Petrovic, A., Pasqualato, S., Dube, P., Krenn, V., Santaguida, S., Cittaro, D., Monzani, S., Massimiliano, L., Keller, J., Tarricone, A. et al. (2010) The MIS12 complex is a protein interaction hub for outer kinetochore assembly. J. Cell Biol., 190, 835-852.
Bolanos-Garcia, V.M., Lischetti, T., Matak-Vinkovic, D., Cota, E., Simpson, P.J., Chirgadze, D.Y., Spring, D.R., Robinson, C.V., Nilsson, J. and Blundell, T.L. (2011) Structure of a Blinkin-BUBR1 complex reveals an interaction crucial for kinetochore-mitotic checkpoint regulation via an unanticipated binding Site. Structure, 19, 1691-1700.
Krenn, V., Wehenkel, A., Li, X., Santaguida, S. and Musacchio, A. (2012) Structural analysis reveals features of the spindle checkpoint kinase Bub1-kinetochore subunit Knl1 interaction. J. Cell Biol., 196, 451-467.
Hanks, S., Coleman, K., Reid, S., Plaja, A., Firth, H., Fitzpatrick, D., Kidd, A., Mehes, K., Nash, R., Robin, N. et al. (2004) Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat. Genet., 36, 1159-1161.
Rauch, A., Thiel, C.T., Schindler, D., Wick, U., Crow, Y.J., Ekici, A.B., van Essen, A.J., Goecke, T.O., Al-Gazali, L., Chrzanowska, K.H. et al. (2008) Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science, 319, 816-819.
Neitzel, H., Neumann, L.M., Schindler, D., Wirges, A., Tonnies, H., Trimborn, M., Krebsova, A., Richter, R. and Sperling, K. (2002) Premature chromosome condensation in humans associated with microcephaly and mental retardation: a novel autosomal recessive condition. Am. J. Hum. Genet., 70, 1015-1022.
Gaspard, N., Bouschet, T., Hourez, R., Dimidschstein, J., Naeije, G., van den Ameele, J., Espuny-Camacho, I., Herpoel, A., Passante, L., Schiffmann, S.N. et al. (2008) An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature, 455, 351-357.
Seelow, D., Schuelke, M., Hildebrandt, F. and Nurnberg, P. (2009) HomozygosityMapper-an interactive approach to homozygosity mapping. Nucleic Acids Res., 37, W593-W599.
Dorus, S., Vallender, E.J., Evans, P.D., Anderson, J.R., Gilbert, S.L., Mahowald, M., Wyckoff, G.J., Malcom, C.M. and Lahn, B.T. (2004) Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell, 119, 1027-1040.
Gaildrat, P., Killian, A., Martins, A., Tournier, I., Frebourg, T. and Tosi, M. (2010) Use of splicing reporter minigene assay to evaluate the effect on splicing of unclassified genetic variants. Methods Mol. Biol., 653, 249-257.