Refining the phenotype associated with CASC5 mutation
Tóm tắt
Autosomal recessive primary microcephaly is a neurodevelopmental disorder characterized by congenitally reduced head circumference by at least two standard deviations (SD) below the mean for age and gender. It is associated with nonprogressive mental retardation of variable degree, minimal neurological deficit with no evidence of architectural anomalies of the brain. So far, 12 genetic loci (MCPH1-12) and corresponding genes have been identified. Most of these encode centrosomal proteins. CASC5 is one the most recently unravelled genes responsible for MCPH with mutations reported in three consanguineous families of Moroccan origin, all of whom harboured the same CASC5 homozygous mutation (c.6125G>A; p.Met2041Ile). Here, we report the identification, by whole exome sequencing, of the same missense mutation in a consanguineous Algerian family. All patients exhibited a similar clinical phenotype, including congenital microcephaly with head circumferences ranging from −3 to −4 standard deviations (SD) after age 5 years, moderate to severe cognitive impairment, short stature (adult height −3 SD), dysmorphic features included a sloping forehead, thick eyebrows, synophris and a low columella. Severe vermis hypoplasia and a large cyst of the posterior fossa were observed in one patient. Close microsatellite markers showed identical alleles in the Algerian the previously and Moroccan patients. This study confirms the involvement of CASC5 in autosomal recessive microcephaly and supports the hypothesis of a founder effect of the c.6125G>A mutation. In addition, this report refines the phenotype of this newly recognized form of primary microcephaly.
Tài liệu tham khảo
Woods CG, Bond J, Enard W (2005) Autosomal recessive primary microcephaly MCPH a review of clinical, molecular, and evolutionary findings. Am J Hum Genet 76(5):717–728
Kaindl AM, Passemard S, Kumar P, Kraemer N, Issa L, Zwirner A, Gerard B, Verloes A, Mani S, Gressens P (2010) Many roads lead to primary autosomal recessive microcephaly. Prog Neurobiol 90(3):363–383. doi:10.1016/j.pneurobio.2009.11.002
Darvish H, Esmaeeli-Nieh MGB, Mohseni M, Ghasemi-Firouzabadi S et al (2010) A clinical and molecular genetics study of 112 Iranian families with primary microcephaly. J Med Genet 47(12):823–828. doi:10.1136/jmg.2009.076398
Murdock DR, Clark GD, Bainbridge MN, Newsham I, Wu YQ, Muzny DM, Cheung SW, Gibbs RA, Ramocki MB (2011) Whole–exome sequencing identifies compound heterozygous mutations in WDR62 insiblings with recurrent polymicrogyria. Am J Med Genet A 155A(9):2071–2077. doi:10.1002/ajmg.a.34165
Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, Flores-Sarnat L, Sergi CM, Topçu M, McDonald MT, Barry BJ, Felie JM, Sunu C, Dobyns WB, Folkerth RD, Barkovich AJ, Walsh CA (2010) Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 42(11):1015–1020. doi:10.1038/ng.683
Roberts E, Hampshire DJ, Pattison L, Springell K, Jafri H, Corry P, Mannon J, Rashid Y, Crow Y, Bond J, Woods CG (2002) Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J Med Genet 39(10):718–721
Shen J, Eyaid W, Mochida GH, Al-Moayyad F, Bodell A, Woods CG, Walsh CA (2005) ASPM mutations identified in patients with primary microcephaly and seizures. J Med Genet 42(9):725–729
Passemard S, Titomanlio L, Elmaleh M, Afenjar A, Alessandri JL, Andria G, De Villemeur TB, Boespflug-Tanguy O, Burglen L et al (2009) Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations. Neurology 73(12):962–969. doi:10.1212/WNL.0b013e3181b8799a
Neitzel H, Neumann LM, Schindler D, Wirges A, Tonnies H, Trimborn M, Krebsova A, Richter R, Sperling K (2002) Premature chromosome condensation inhumans associated with microcephaly and mental retardation: a novel autosomal recessive condition. Am J Hum Genet 70(4):1015–1022
Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP (2004) Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet 75(2):261–266
Desir J, Cassart M, David P, Van Bogaert P, Abramowicz M (2008) Primary microcephaly with ASPM mutation shows simplified cortical gyration with anteroposterior gradient pre- and post-natally. Am J Med Genet A 146A(11):1439–1443. doi:10.1002/ajmg.a.32312
Saadi A, Borck G, Boddaert N, Chekkour MC, Imessaoudene B, Munnich A, Colleaux L, Chaouch M (2009) Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family. Eur J Med Genet 52(4):180–184. doi:10.1016/j.ejmg.2009.03.013
Bilgüvar K, Oztürk AK, Louvi A, Kwan KY, Choi M, Tatli B, Yalnizoğlu D, Tüysüz B, Cağlayan AO, Gökben S, Kaymakçalan H, Barak T, Bakircioğlu M, Yasuno K, Ho W, Sanders S, Zhu Y et al (2010) Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467(7312):207–210. doi:10.1038/nature09327
Bhat V, Girimaji SC, Mohan G, Arvinda HR, Singhmar P, Duvvari MR, Kumar A (2011) Mutations in WDR62, encoding a centrosomal and nuclear protein, in Indian primary microcephaly families with cortical malformations. Clin Genet 80(6):532–540. doi:10.1111/j.1399-0004.2011.01686.x
Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG (2002) Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71(1):136–142
Nicholas AK, Khurshid M, Désir J, Carvalho OP, Cox JJ, Thornton G, Kausar R, Ansar M, Ahmad W, Verloes A, Passemard S, Misson JP, Lindsay S, Gergely F, Dobyns WB, Roberts E, Abramowicz M, Woods CG (2010) WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 42(11):1010–1014. doi:10.1038/ng.682
Bond J, Roberts E, Springell K, Lizarraga SB, Scott S, Higgins J, Hampshire DJ, Morrison EE, Leal GF, Silva EO, Costa SM, Baralle D, Raponi M, Karbani G, Rashid Y, Jafri H, Bennett C, Corry P, Walsh CA, Woods CG (2005) A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 37(4):353–355
Genin A, Desir J, Lambert N, Biervliet M, Van Der Aa N, Pierquin G, Killian A, Tosi M, Urbina M, Lefort A, Libert F, Pirson I, Abramowicz M (2012) Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum Mol Genet 21(24):5306–5317. doi:10.1093/hmg/dds386
Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG (2002) ASPM is a major determinant of cerebral cortical size. Nat Genet 32(2):316–320
Kumar A, Girimaji SC, Duvvari MR, Blanton SH (2009) Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. Am J Hum Genet 84(2):286–290. doi:10.1016/j.ajhg.2009.01.017
Hussain MS, Baig SM, Neumann S, Nürnberg G, Farooq M, Ahmad I, Alef T, Hennies HC, Technau M, Altmüller J, Frommolt P, Thiele H, Noegel AA, Nürnberg P (2012) A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am J Hum Genet 90(5):871–878. doi:10.1016/j.ajhg.2012.03.016
Guernsey DL, Jiang H, Hussin J, Arnold M, Bouyakdan K, Perry S, Babineau-Sturk T, Beis J, Dumas N, Evans SC, Ferguson M, Matsuoka M, Macgillivray C, Nightingale M, Patry L, Rideout AL, Thomas A, Orr A, Hoffmann I, Michaud JL, Awadalla P, Meek DC, Ludman M, Samuels ME (2010) Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am J Hum Genet 87(1):40–51. doi:10.1016/j.ajhg.2010.06.003
Yang YJ, Baltus AE, Mathew RS, Murphy EA, Evrony GD, Gonzalez DM, Wang EP, Marshall-Walker CA, Barry BJ, Murn J, Tatarakis A, Mahajan MA, Samuels HH, Shi Y, Golden JA, Mahajnah M, Shenhav R, Walsh CA (2012) Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation. Cell 151(5):1097–1112. doi:10.1016/j.cell.2012.10.043
Awad S, Al-Dosari MS, Alyacoub N, Colak D, Salih MA, Alkuraya FS, Poizat C (2013) Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. Hum Mol Genet 22(11):2200–2213. doi:10.1093/hmg/ddt072
Hussain MS, Baig SM, Neumann S, Peche VS, Szczepanski S, Nürnberg G, Tariq M, Jameel M, Naeem T, Fatima A, Malik NA, Ahmad I, Altmüller J, Frommolt P, Thiele H, Höhne W, Yigit G, Wollnik B, Neubauer BA, Nürnberg P, Noegel AA (2013) CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly. Hum Mol Genet 22(25):5199–5214. doi:10.1093/hmg/ddt374
Cheeseman IM, Hori T, Fukagawa T, Desai A (2008) KNL1 and the CENP-H/I/K complex coordinately direct kinetochore assembly in vertebrates. Mol Biol Cell 19(2):587–594
Bolanos-Garcia VM, Lischetti T, Matak-Vinkovic D et al (2011) Structure of a Blinkin-BUBR1 complex reveals an interaction crucial for kinetochore-mitotic checkpoint regulation via an unanticipated binding Site,”. Structure 19(11–12):1691–1700. doi:10.1016/j.str.2011.09.017
Rio M, Molinari F, Heuertz S, Ozilou C, Gosset P, Raoul O, Cormier-Daire V, Amiel J, Lyonnet S, Le Merrer M, Turleau C, de Blois MC, Prieur M, Romana S, Vekemans M, Munnich A, Colleaux L (2002) Automated fluorescent genotyping detects 10% of cryptic subtelomeric rearrangements in idiopathic syndromic mental retardation. J Med Genet 39(4):266–270
Kiyomitsu T, Murakami H, 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(5):998–1011. doi:10.1128/MCB.00815-10
Petrovic A, Pasqualato S, Dube P, Krenn V, Santaguida S, Cittaro D, Monzani S, Massimiliano L, Keller J, Tarricone A, Maiolica A, Stark H, Musacchio A (2010) The MIS12 complex is a protein interaction hub for outer kinetochore assembly. J Cell Biol 190(5):835–852. doi:10.1083/jcb.201002070
Al-Dosari MS, Shaheen R, Colak D, Alkuraya FS (2010) Novel CENPJ mutation causes Seckel syndrome. J Med Genet 47(6):411–414. doi:10.1136/jmg.2009.076646
Kalay E, Yigit G, Aslan Y, Brown KE, Pohl E, Bicknell LS, Kayserili H, Li Y, Tüysüz B, Nürnberg G, Kiess W, Koegl M, Baessmann I, Buruk K, Toraman B, Kayipmaz S, Kul S, Ikbal M, Turner DJ, Taylor MS, Aerts J, Scott C, Milstein K, Dollfus H, Wieczorek D, Brunner HG, Hurles M, Jackson AP, Rauch A, Nürnberg P, Karagüzel A, Wollnik B (2011) CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet 43(1):23–26. doi:10.1038/ng.725
Mirzaa GM, Vitre B, Carpenter G, Abramowicz I, Gleeson JG, Pachiorkowski AR, Cleveland DW, Dobyns WB, O'Driscoll M (2014) Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. Hum Genet 133(8):1023–1039. doi:10.1007/s00439-014-1443-3
Poulton CJ, Schot R, Seufert K, Lequin MH, Accogli A, Annunzio GD, Villard L, Philip N, de Coo R, Catsman-Berrevoets C, Grasshoff U, Kattentidt-Mouravieva A, Calf H, de Vreugt-Gronloh E, van Unen L, Verheijen FW, Galjart N, Morris-Rosendahl DJ, Mancini GM (2014) Severe presentation of WDR62 mutation: is there a role for modifying genetic factors? Am J Med Genet A 164A(9):2161–2171. doi:10.1002/ajmg.a.36611