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Developmental genetic malformations of the cerebral cortex

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Abstract

Cortical malformations give rise to severe clinical manifestations such as epilepsy and mental retardation, but sometimes to more subtle problems like dyslexia. From a clinical standpoint, such structural abnormalities are diagnosed by radiographic and histologic findings, with disease classifications often based on these observations. Using this categorization, many of the responsible genes have been determined and now provide a means of understanding the molecular basis of the neurologic disorders. This review discusses the known genetic developmental syndromes in the context of the observed cortical malformations, the expression and function of the responsible genes, and their potential roles during the various stages of central nervous system development.

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References and Recommended Reading

  1. Jacobsen M: Developmental Neurobiology. New York: Plenum Press; 1991.

    Google Scholar 

  2. Mochida GH, Walsh CA: Molecular genetics of human microcephaly. Curr Opin Neurol 2001, 14:151–156.

    Article  PubMed  CAS  Google Scholar 

  3. Opitz J, Ho MC: Microcephaly:general considerations and aids to nosology. J Craniofac Genet Dev Biol 1990, 10:175–204.

    PubMed  CAS  Google Scholar 

  4. Mochida GH, Krisnamoorthy K: Microcephaly. In Neurobase. Edited by Gilman S, Waxman S. San Diego: Arbor Publishing; 2000.

    Google Scholar 

  5. Sabry M, Mochida G, Walsh C: Emery and Rimoin’s Principles and Practice of Medical Genetics, edn 4. Edited by Rimoin D. Boston: Churchill Livingstone; 2001.

    Google Scholar 

  6. Bond J, Roberts E, Mochida GH, et al.: ASPM is a major determinant of cerebral cortical size. Nat Genet 2002, 32:316–320.

    Article  PubMed  CAS  Google Scholar 

  7. do Carmo Avides M, Glover DM: Abnormal spindle protein, Asp, and the integrity of mitotic centrosomal microtubule organizing centers. Science 1999, 283:1733–1735.

    Article  PubMed  Google Scholar 

  8. Jackson AP, Eastwood H, Bell SM, et al.: Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 2002, 71:136–142.

    Article  PubMed  CAS  Google Scholar 

  9. Huyton T, Bates PA, Zhang X, et al.: The BRCA1 C-terminal domain: structure and function. Mutat Res 2000, 460:319–332.

    PubMed  CAS  Google Scholar 

  10. Rosenberg MJ, Agarwala R, Bouffard G, et al.: Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nat Genet 2002, 32:175–179.

    Article  PubMed  CAS  Google Scholar 

  11. Matsura S, Tauchi H, Nakamura A, et al.: Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet 1998, 19:179–181.

    Article  CAS  Google Scholar 

  12. Carney JP, Maser RS, Olivares H, et al.: The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 1998, 93:477–486.

    Article  PubMed  CAS  Google Scholar 

  13. Wu X, Ranganathan V, Weisman DS, et al.: ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 2000, 405:477–482.

    Article  PubMed  CAS  Google Scholar 

  14. Poussaint TY, Fox JW, Dobyns WB, et al.: Periventricular nodular heterotopia in patients with filamin-1 gene mutations: neuroimaging findings. Pediatr Radiol 2000, 30:748–755.

    Article  PubMed  CAS  Google Scholar 

  15. Fox JW, Lamperti ED, Eksioglu YZ, et al.: Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 1998, 21:1315–1325.

    Article  PubMed  CAS  Google Scholar 

  16. Sheen VL, Wheless JW, Bodell A, et al.: Periventricular heterotopia associated with chromosome 5p anomalies. Neurology 2003, 60:1033–1036.

    PubMed  CAS  Google Scholar 

  17. Sheen VL, Topcu M, Berkovic S, et al.: Autosomal recessive form of periventricular heterotopia. Neurology 2003, 60:1108–1112.

    PubMed  CAS  Google Scholar 

  18. Gorlin JB, Yamin R, Egan S, et al.: Human endothelial actinbinding protein (ABP-280, nonmuscle filamin): a molecular leaf spring. J Cell Biol 1990, 111:1089–1105.

    Article  PubMed  CAS  Google Scholar 

  19. Dulabon L, Olson EC, Taglienti MG, et al.: Reelin binds _3_1 integrin and inhibits neuronal migration. Neuron 2000, 27:33–44.

    Article  PubMed  CAS  Google Scholar 

  20. Sheen VL, Feng Y, Graham D, et al.: Filamin A and Filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact. Hum Mol Genet 2002, 11:2845–2854.

    Article  PubMed  CAS  Google Scholar 

  21. Nagano T, Yoneda T, Hatanaka Y, et al.: Filamin A-interacting protein (FILIP) regulates cortical cell migration out of the ventricular zone. Nat Cell Biol 2002, 4:495–501.

    PubMed  CAS  Google Scholar 

  22. Tu Y, Wu S, Shi X, et al.: Migfilin and mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation. Cell 2003, 113:37–47. The authors demonstrate that Mig-2 recruits migfilin to cell-matrix adhesions, whereas the interaction with filamin mediates the association of migfilin with actin filaments. Disruption of these focal adhesions provides a potential explanation for failure of neurons to attach onto radial glia and exit the ventricular zone.

    Article  PubMed  CAS  Google Scholar 

  23. Togawa A, Morinaga N, Ogasawara M, et al.: Purification and cloning of a brefeldin A-inhibited guanine nucleotideexchange protein for ADP-ribosylation factors. J Biol Chem 1999, 274:12308–12315.

    Article  PubMed  CAS  Google Scholar 

  24. Pacheco-Rodriguez G, Moss J, Vaughan M: BIG1 and BIG2: brefeldin A-inhibited guanine nucleotide-exchange proteins for ADP-ribosylation factors. Methods Enzymol 2002, 345:397–404.

    Article  PubMed  Google Scholar 

  25. Jareb M, Banker G: Inhibition of axonal growth by brefeldin A in hippocampal neurons in culture. J Neurosci 1997, 17:8955–8963.

    PubMed  CAS  Google Scholar 

  26. Ruthel G, Banker G: Role of moving growth cone-like "wave" structures in the outgrowth of cultured hippocampal axons and dendrites. J Neurobiol 1999, 39:97–106.

    Article  PubMed  CAS  Google Scholar 

  27. Rakic P: Specification of cerebral cortical areas. Science 1988, 241:170–176.

    Article  PubMed  CAS  Google Scholar 

  28. Anderson S, Mione M, Yun K, Rubenstein JL: Differential origins of neocortical projection and local circuit neurons: role of Dlx genes in neocortical interneuronogenesis. Cereb Cortex 1999, 9:646–654.

    Article  PubMed  CAS  Google Scholar 

  29. Infante JP, Huszagh VA: On the molecular etiology of decreased arachadonic (20:4n-6), docosapentaenoic (22:5n-6) and docosohexaenoic (22:6n-3) acids in Zellweger syndrome and other peroxisomal disorders. Mol Cell Biochem 1997, 168:101–115.

    Article  PubMed  CAS  Google Scholar 

  30. Gleeson JG, Allen KM, Fox JW, et al.: Doublecortin, a brainspecific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998, 92:63–72.

    Article  PubMed  CAS  Google Scholar 

  31. Reiner, O, R Carrozzo, Y Shen, et al.: Isolation of a Miller-Dieker lissencephaly gene containing G protein betasubunit-like repeats. Nature 1993, 364:717–721.

    Article  PubMed  CAS  Google Scholar 

  32. Hong, SE, YY Shugart, DT Huang, et al.: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 2001, 27:225.

    Article  CAS  Google Scholar 

  33. Gleeson, JG, PT Lin, LA Flanagan, Walsh CA: Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 1999, 23:257–271.

    Article  PubMed  CAS  Google Scholar 

  34. Niethammer, M, DS Smith, R Ayala, et al.: NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Neuron 2000, 28:697–711.

    Article  PubMed  CAS  Google Scholar 

  35. Caspi M, Atlas R, Kantor A, et al.: Interaction between LIS1 and doublecortin, two lissencephaly gene products. Hum Mol Genet 2000, 9:2205–2213. The authors show by co-immunoprecipitation and microtubule polymerization assays that LIS1 and DCX physically and functionally interact, thereby implicating a common pathway in formation of classical lissencephaly.

    PubMed  CAS  Google Scholar 

  36. Feng Y, Olson EC, Stukenberg PT, et al.: LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron 2000, 28:665–679.

    Article  PubMed  CAS  Google Scholar 

  37. Efimov VP, Morris NR: The LIS1-related NUDF protein of Aspergillus nidulans interacts with the coiled-coil domain of the NUDE/RO11 protein. J Cell Biol 2000, 150:681–688.

    Article  PubMed  CAS  Google Scholar 

  38. Trommsdorff M, Gotthardt M, Hiesberger T, et al.: Reeler/ Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 1999, 97:689–701.

    Article  PubMed  CAS  Google Scholar 

  39. Bonneau D, Toutain A, Laquerriere A, et al.: X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings. Ann Neurol 2002, 51:340–349.

    Article  PubMed  Google Scholar 

  40. Kitamura K, Yanazawa M, Sugiyama N, et al.: Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 2002, 32:359–369.

    Article  PubMed  CAS  Google Scholar 

  41. Fukuyama Y, Osawa M, Suzuki H: Congenital progressive muscular dystrophy of the Fukuyama type -clinical, genetic and pathological considerations. Brain Dev 1981, 3:1–29.

    PubMed  CAS  Google Scholar 

  42. Dobyns WB, Pagon RA, Armstrong D, et al.: Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 1989, 32:195–210.

    Article  PubMed  CAS  Google Scholar 

  43. Kobayashi K, Nakahori Y, Miyake M, et al.: An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998, 394:388–392.

    Article  PubMed  CAS  Google Scholar 

  44. Beltran-Valero De Bernabe D, Currier S, Steinbrecher A, et al.:Mutations in the O-Mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002, 71:1033–1043.

    Article  Google Scholar 

  45. Yoshida A, Kobayashi K, Manya H, et al.: Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 2001, 1:717–724.

    Article  PubMed  CAS  Google Scholar 

  46. Michele DE, Barresi R, Kanagawa M, et al.: Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 2002, 418:417–422. The authors demonstrate a convergent post-translational processing pathway for MEB and FKMD during the biosynthesis of dystroglycan, and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with cobblestone lissencephaly.

    Article  PubMed  CAS  Google Scholar 

  47. Moore SA, Saito F, Chen J, et al.: Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 2002, 418:422–425. The authors demonstrate a convergent post-translational processing pathway for MEB and FKMD during the biosynthesis of dystroglycan, and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with cobblestone lissencephaly.

    Article  PubMed  CAS  Google Scholar 

  48. Kano H, Kobayashi K, Herrmann R, et al.: Deficiency of alphadystroglycan in muscle-eye-brain disease. Biochem Biophys Res Commun 2002, 291:1283–1286.

    Article  PubMed  CAS  Google Scholar 

  49. Piao X, Basel-Vanagaite L, Straussberg R, et al.: An autosomal recessive form of bilateral frontoparietal polymicrogyria maps to chromosome 16q12.2-21. Am J Hum Genet 2002, 70:1028–1033.

    Article  PubMed  CAS  Google Scholar 

  50. Barkovich AJ, Hevnet R, Guerrini R: Syndromes of bilateral symmetrical polymicrogyria. Am J Neuroradiol 1999, 20:1814–1821.

    PubMed  CAS  Google Scholar 

  51. Henske EP, Scheithauer BW, Short MP, et al.: Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 1996, 59:400–406.

    PubMed  CAS  Google Scholar 

  52. Lamb RF, Roy C, Diefenbach TJ, et al.: The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat Cell Biol 2000, 2:281–287.

    Article  PubMed  CAS  Google Scholar 

  53. Soucek T, Yeung RS, Hengstschlager M: Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2. Proc Natl Acad Sci U S A 1998, 95:15653–15658.

    Article  PubMed  CAS  Google Scholar 

  54. van Slegtenhorst M, Nellist M, Nagelkerken B, et al.: Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 1998, 7:1053–1057.

    Article  PubMed  Google Scholar 

  55. Faiella A, Brunelli S, Granata T, et al.: A number of schizencephaly patients including 2 brothers are heterozygous for germline mutations in the homeobox gene EMX2. Eur J Hum Genet 1997, 5:186–190.

    PubMed  CAS  Google Scholar 

  56. Granata T, Farina L, Faiella A, et al.: Familial schizencephaly associated with EMX2 mutation. Neurology 1997, 48:1403–1406.

    PubMed  CAS  Google Scholar 

  57. Simeone A, Acampora D, Gulisano M, et al.: Nested expression domains of four homeobox genes in developing rostral brain. Nature 1992, 358:687–690.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Beth Israel Deaconess Medical Center, HIM 816, 4 Blackfan Circle, 02115, Boston, MA, USA

    Volney L. Sheen MD, PhD & Christopher A. Walsh MD, PhD

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  1. Volney L. Sheen MD, PhD
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  2. Christopher A. Walsh MD, PhD
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Sheen, V.L., Walsh, C.A. Developmental genetic malformations of the cerebral cortex. Curr Neurol Neurosci Rep 3, 433–441 (2003). https://doi.org/10.1007/s11910-003-0027-8

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