Advertisement

Human Genetics

, Volume 131, Issue 1, pp 99–110 | Cite as

Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH)

  • Shin Hayashi
  • Nobuhiko Okamoto
  • Yasutsugu Chinen
  • Jun-ichi Takanashi
  • Yoshio Makita
  • Akira Hata
  • Issei Imoto
  • Johji Inazawa
Original Investigation

Abstract

The CASK gene encoding a member of the membrane-associated guanylate kinase protein family is highly expressed in the mammalian nervous system of both adults and fetuses, playing several roles in neural development and synaptic function. Recently, CASK aberrations caused by both mutations and deletions have been reported to cause severe mental retardation (MR), microcephaly and disproportionate pontine and cerebellar hypoplasia (MICPCH) in females. Here, mutations and copy numbers of CASK were examined in ten females with MR and MICPCH, and the following changes were detected: nonsense mutations in three cases, a 2-bp deletion in one case, mutations at exon–intron junctions in two cases, heterozygous deletions encompassing CASK in two cases and interstitial duplications in two cases. Except for the heterozygous deletions, each change including the intragenic duplications potentially caused an aberrant transcript, resulting in CASK null mutations. The results provide novel mutations and copy number aberrations of CASK, causing MR with MICPCH, and also demonstrate the similarity of the phenotypes of MR with MICPCH regardless of the CASK mutation.

Keywords

Mental Retardation Bacterial Artificial Chromosome Prime Combination Premature Stop Codon Splice Acceptor Site 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Ayako Takahashi and Rumi Mori for technical assistance. This study was supported by the Joint Usage/Research Program of Medical Research Institute, Tokyo Medical and Dental University. This work was also supported by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; a grant from Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Corporation (JST); a grant from the New Energy and Industrial Technology Development Organization (NEDO).

Supplementary material

439_2011_1047_MOESM1_ESM.pdf (178 kb)
Supplementary material 1 (PDF 396 kb)

References

  1. Atasoy D, Schoch S, Ho A, Nadasy KA, Liu X, Zhang W, Mukherjee K, Nosyreva ED, Fernandez-Chacon R, Missler M, Kavalali ET, Südhof TC (2007) Deletion of CASK in mice is lethal and impairs synaptic function. Proc Natl Acad Sci USA 104:2525–2530PubMedCrossRefGoogle Scholar
  2. Chao HW, Hong CJ, Huang TN, Lin YL, Hsueh YP (2008) SUMOylation of the MAGUK protein CASK regulates dendritic spinogenesis. J Cell Biol 182:141–155PubMedCrossRefGoogle Scholar
  3. Cohen AR, Woods DF, Marfatia SM, Walther Z, Chishti AH, Anderson JM (1998) Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells. J Cell Biol 142:129–138PubMedCrossRefGoogle Scholar
  4. D’Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T (1995) A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374:719–723PubMedCrossRefGoogle Scholar
  5. Hata Y, Butz S, Südhof TC (1996) CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J Neurosci 16:2488–2494PubMedGoogle Scholar
  6. Hayashi S, Kurosawa K, Imoto I, Mizutani S, Inazawa J (2005) Detection of cryptic chromosome aberrations in a patient with a balanced t(1;9)(p34.2;p24) by array-based comparative genomic hybridization. Am J Med Genet A 139:32–36PubMedGoogle Scholar
  7. Hayashi S, Honda S, Minaguchi M, Makita Y, Okamoto N, Kosaki R, Okuyama T, Imoto I, Mizutani S, Inazawa J (2007) Construction of a high-density and high-resolution human chromosome X array for comparative genomic hybridization analysis. J Hum Genet 52:397–405PubMedCrossRefGoogle Scholar
  8. Hayashi S, Mizuno S, Migita O, Okuyama T, Makita Y, Hata A, Imoto I, Inazawa J (2008) The CASK gene harbored in a deletion detected by array-CGH as a potential candidate for a gene causative of X-linked dominant mental retardation. Am J Med Genet A 146A:2145–2151PubMedCrossRefGoogle Scholar
  9. Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA (2000) Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with RELN mutations. Nat Genet 26:93–96PubMedCrossRefGoogle Scholar
  10. Hsueh YP (2006) The role of the MAGUK protein CASK in neural development and synaptic function. Curr Med Chem 13:1915–1927PubMedCrossRefGoogle Scholar
  11. Hsueh YP (2009) Calcium/calmodulin-dependent serine protein kinase and mental retardation. Ann Neurol 66:438–443PubMedCrossRefGoogle Scholar
  12. Hsueh YP, Wang TF, Yang FC, Sheng M (2000) Nuclear transcription and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 404:298–302PubMedCrossRefGoogle Scholar
  13. Inazawa J, Inoue J, Imoto I (2004) Comparative genomic hybridization (CGH)-arrays pave the way for identification of novel cancer-related genes. Cancer Sci 95:559–563PubMedCrossRefGoogle Scholar
  14. Inoue K, Osaka H, Thurston VC, Clarke JT, Yoneyama A, Rosenbarker L, Bird TD, Hodes ME, Shaffer LG, Lupski JR (2002) Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am J Hum Genet 71:838–853PubMedCrossRefGoogle Scholar
  15. Irie M, Hata Y, Takeuchi M, Ichtchenko K, Toyoda A, Hirao K, Takai Y, Rosahl TW, Südhof TC (1997) Binding of neuroligins to PSD-95. Science 277:1511–1515PubMedCrossRefGoogle Scholar
  16. Laverty HG, Wilson JB (1998) Murine CASK is disrupted in a sex-linked cleft palate mouse mutant. Genomics 53:29–41PubMedCrossRefGoogle Scholar
  17. Najm J, Horn D, Wimplinger I, Golden JA, Chizhikov VV, Sudi J, Christian SL, Ullmann R, Kuechler A, Haas CA, Flubacher A, Charnas LR, Uyanik G, Frank U, Klopocki E, Dobyns WB, Kutsche K (2008) Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet 40:1065–1067PubMedCrossRefGoogle Scholar
  18. Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K, Yamamoto H, Mikoshiba K (1995) The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 14:899–912PubMedCrossRefGoogle Scholar
  19. Olsen O, Moore KA, Fukata M, Kazuta T, Trinidad JC, Kauer FW, Streuli M, Misawa H, Burlingame AL, Nicoll RA, Bredt DS (2005) Neurotransmitter release regulated by a MALS–liprin–alpha presynaptic complex. J Cell Biol 170:1127–1134PubMedCrossRefGoogle Scholar
  20. Piluso G, D’Amico F, Saccone V, Bismuto E, Rotundo IL, Di Domenico M, Aurino S, Schwartz CE, Neri G, Nigro V (2009) A missense mutation in CASK causes FG syndrome in an Italian family. Am J Hum Genet 84:162–177PubMedCrossRefGoogle Scholar
  21. Rice DS, Sheldon M, D’Arcangelo G, Nakajima K, Goldowitz D, Curran T (1998) Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Development 125:3719–3729PubMedGoogle Scholar
  22. Saito-Ohara F, Fukuda Y, Ito M, Agarwala KL, Hayashi M, Matsuo M, Imoto I, Yamakawa K, Nakamura Y, Inazawa J (2002) The Xq22 inversion breakpoint interrupted a novel Ras-like GTPase gene in a patient with Duchenne muscular dystrophy and profound mental retardation. Am J Hum Genet 71:637–645PubMedCrossRefGoogle Scholar
  23. Shaffer LG, Tommerup N (2005) An International System for Human Cytogenetic Nomenclature (2005). Karger, BaselGoogle Scholar
  24. Stankiewicz P, Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends Genet 18:74–82PubMedCrossRefGoogle Scholar
  25. Stevenson D, Laverty HG, Wenwieser S, Douglas M, Wilson JB (2000) Mapping and expression analysis of the human CASK gene. Mammalian Genome 11:934–937PubMedCrossRefGoogle Scholar
  26. Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O’Meara S, Latimer C, Dicks E, Menzies A, Stephens P, Blow M, Greenman C, Xue Y, Tyler-Smith C, Thompson D, Gray K, Andrews J, Barthorpe S, Buck G, Cole J, Dunmore R, Jones D, Maddison M, Mironenko T, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Teague J, Butler A, Jenkinson A, Jia M, Richardson D, Shepherd R, Wooster R, Tejada MI, Martinez F, Carvill G, Goliath R, de Brouwer AP, van Bokhoven H, van Esch H, Chelly J, Raynaud M, Ropers HH, Abidi FE, Srivastava AK, Cox J, Luo Y, Mallya U, Moon J, Parnau J, Mohammed S, Tolmie JL, Shoubridge C, Corbett M, Gardner A, Haan E, Rujirabanjerd S, Shaw M, Vandeleur L, Fullston T, Easton DF, Boyle J, Partington M, Hackett A, Field M, Skinner C, Stevenson RE, Bobrow M, Turner G, Schwartz CE, Gecz J, Raymond FL, Futreal PA, Stratton MR (2009) A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet 41:535–543PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Shin Hayashi
    • 1
    • 2
  • Nobuhiko Okamoto
    • 3
  • Yasutsugu Chinen
    • 4
  • Jun-ichi Takanashi
    • 5
  • Yoshio Makita
    • 6
  • Akira Hata
    • 7
  • Issei Imoto
    • 1
    • 8
  • Johji Inazawa
    • 1
    • 9
  1. 1.Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical ScienceTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Hard Tissue Genome Research Center, Tokyo Medical and Dental UniversityTokyoJapan
  3. 3.Department of Planning and ResearchOsaka Medical Center and Research Institute for Maternal and Child HealthOsakaJapan
  4. 4.Department of PediatricsUniversity of the Ryukyu School of MedicineOkinawaJapan
  5. 5.Department of PediatricsKameda Medical CenterChibaJapan
  6. 6.Education Center, Asahikawa Medical CollegeAsahikawaJapan
  7. 7.Department of Public HealthChiba University Graduate School of MedicineChibaJapan
  8. 8.Department of Human Genetics and Public Health Graduate School of Medical ScienceThe University of TokushimaTokushimaJapan
  9. 9.Global Center of Excellence (GCOE) Program for ‘International Research Center for Molecular Science in Tooth and Bone Diseases’Tokyo Medical and Dental UniversityTokyoJapan

Personalised recommendations