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• W2038567507 abstract "If flies had a cerebral cortex, figuring out how it developed would be relatively simple. You could perform deliberate, random mutagenesis and screen flies for cortical abnormalities behaviorally, and you could examine them anatomically. You could group mutant flies according to their cortical phenotype, since different genes that cause similar phenotypes probably encode proteins that relate somehow in a biochemical pathway. Finally, you could order the mutated genes into epistatic relationships by performing specific breeding experiments. Although the genetics of humans is not as malleable as that of the fly, millions of unfortunate individuals who suffer from cortical malformations attest to the fact that Nature has already performed widespread random mutagenesis on the human brain, producing a rich variety of mutations that disrupt cortical development in specific and surprising ways. Moreover, humans live under essentially constant behavioral screening of the cortex—we call it school, work, and play. Therefore, even subtle anomalies manifested by a single seizure or a mild learning disorder are usually detected. Rapid, noninvasive imaging of the human cortex (e.g., magnetic resonance imaging [MRI]) can link behavioral phenotypes to gross anatomical anomalies in a little more time than it takes to examine the fly’s CNS. Although humans were formerly considered difficult subjects for positional cloning, technical limitations are rapidly vanishing. With genetic maps of ever-higher density, gene identification from small pedigrees or even single individuals with informative chromosomal rearrangements has become possible. But the richness of the genetics remains the cardinal feature of the human brain: human cortical malformations are frequently “genetically heterogeneous,” meaning that more than one gene can cause a similar or identical phenotype when mutated. This property, formerly regarded as a major technical nuisance (because it complicates gene mapping studies), now appears as a golden opportunity to sketch out genetic pathways that can be fleshed out by in vitro studies and animal models. Like any mutational screen, the one that affects humans is probably not complete. It is biased toward dominant and X-linked traits, and against recessives, given the common Western societal restrictions against consanguineous marriages. However, other major populations prefer consanguineous marriages for cultural reasons, allowing even autosomal recessive disorders to be seen with surprising frequency. The human mutational screen also is biased against detecting embryonic lethal phenotypes, but not as severely as might be expected because of the unique size of the human brain. Since cells in the human cortex undergo so many rounds of mitosis, spontaneous somatic mutations that produce mosaic brains of normal and mutant cells appear to be surprisingly common and allow analysis of otherwise lethal mutations in naturally occurring mosaics. This review outlines human genetic disorders that produce a morphologically abnormal cerebral cortex. Other disorders are associated with a grossly normal cortex that nonetheless does not function properly—such as inherited epilepsy or mental retardation—or disturb the development of CNS glia, but these disorders are not covered for space reasons. I will also focus primarily on disorders in which the genetics and pathology are reasonably well characterized, rather than on disorders—such as schizophrenia—for which morphological disorders of the cortex have been reported but which are less cut and dried. Since this review provides a brief overview of a vast literature, I apologize at the outset for much important work that cannot be cited because of space constraints. The most common result of severe cortical malformations is profound mental impairment, epilepsy, and limb paralysis. It is therefore surprising that some individuals with dramatic brain malformations have remarkably normal intelligence and are detected only because of their epilepsy. Overall, morphological abnormalities of the cortex account for a substantial fraction (5%–15%) of epilepsy in adults (47Hardiman O Burke T Phillips J Murphy S O’Moore B Staunton H Farrell M.A Microdysgenesis in resected temporal neocortex incidence and clinical significance in focal epilepsy.Neurology. 1988; 38: 1041-1047Crossref PubMed Google Scholar, 11Brodtkorb E Nilsen G Smevik O Rinck P.A Epilepsy and anomalies of neuronal migration MRI and clinical aspects.Acta Neurol. Scand. 1992; 86: 24-32Crossref PubMed Scopus (98) Google Scholar, 49Hauser W.A Annegers J.F Kurland L.T Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota 1935–1984.Epilepsia. 1993; 34: 453-468Crossref PubMed Scopus (1738) Google Scholar) and a higher proportion of epilepsy in children. However, the types of malformations seen are highly variable in any given series of patients studied, because the malformations are heterogeneous genetically, and because each malformation is individually rare (typically occurring in <1/10,000 people). Consequently, collection of sufficient numbers of patients with a specific malformation for genetic studies typically requires widespread, international collaboration. The mechanisms of genes that cause human malformations have traditionally been roughly inferred from the locus of the malformation, but this information is increasingly being supplanted by more complete analysis in mouse models. Since neurons destined for the cortex are formed from progenitor cells located deep in the brain, along the lateral ventricles, malformations that produce collections of cells in the ventricular zone are interpreted as reflecting genes involved in cell proliferation and cell fate, particularly if the abnormally located cells also appear morphologically abnormal. Since neurons subsequently migrate from the ventricular zone to the cortex, there are a number of disorders that cause the accumulation of neurons at a variety of locations between the ventricular zone and the cortex and thus are thought to disturb neuronal migration. Although terms such as “neuronal migration disorder” are only a first approximation when discussing human disorders, they are nonetheless common parlance. Unfortunately, many human syndromes were first described a century ago by pathologists, before genetics or neurobiology was well established. Hence, terminology is generally imprecise and in Greek, with the classification of many cortical disorders relying on descriptions of the alterations in the patterns of gyri and sulci, since these are most readily visible radiographically or at postmortem examination. However, since the advent of disease gene cloning, it has been recognized that there is an imperfect correlation between abnormal patterns of gyration and specific histological structures or genetic conditions: mutations in the same gene can cause a range of gyral abnormalities, and a given gyral pattern can be caused by more than one gene. Recently, efforts have been made to systematize the classification of cortical malformations (8Barkovich A.J Kuzniecky R.I Dobyns W.B Jackson G.D Becker L.E Evrard P A classification scheme for malformations of cortical development.Neuropediatrics. 1996; 27: 59-63Crossref PubMed Scopus (362) Google Scholar). The classifications used in this article should not be considered definitive. Classifications will improve as better morphological information becomes available, and as genes underlying specific conditions become identified and provide clearer insight for use in mechanistic classifications. During normal development, the early forebrain (a.k.a. prosencephalon) divides and gives rise to the two cerebral hemispheres. In holoprosencephaly (HPE), there is failure of the normal midline separation of the two hemispheres resulting in a single forebrain ventricle and a single forebrain. There is continuity of the gray matter of the two cerebral hemispheres across the midline (Figure 1A and Figure 1B). Holoprosencephaly is not rare by the standards of a genetic disease, affecting 0.58–1.2/10,000 births (84Rasmussen S.A Moore C.A Khoury M.J Cordero J.F Descriptive epidemiology of holoprosencephaly and arhinencephaly in metropolitan Atlanta, 1968–1992.Am. J. Med. Genet. 1996; 66: 320-333Crossref PubMed Scopus (58) Google Scholar). At least 12 chromosomal regions on 11 chromosomes have been implicated as HPE loci by either chromosomal anomalies or in some cases by linkage analysis (39Golden J.A Holoprosencephaly a defect in brain patterning.J. Neuropathol. Exp. Neurol. 1998; 57: 991-999Crossref PubMed Scopus (91) Google Scholar, 72Ming J.E Muenke M Holoprosencephaly from Homer to Hedgehog.Clin. Genet. 1998; 53: 155-163Crossref PubMed Scopus (115) Google Scholar), suggesting the potential for a remarkable genetic dissection of a dramatic morphogenetic event. So far, two HPE genes have been identified in humans, and there is preliminary evidence for three more. HPE3 (chromosome 7q36) is caused by heterozygous mutations in the sonic hedgehog gene (SHH) (87Roessler E Belloni E Gaudenz K Jay P Berta P Scherer S.W Tsui L.C Muenke M Mutations in the human Sonic Hedgehog gene cause holoprosencephaly.Nat. Genet. 1996; 14: 357-360Crossref PubMed Scopus (947) Google Scholar). SHH encodes a secreted protein required for ventral induction throughout the neuraxis, as well as for positional specification in the limb and elsewhere (41Goodrich L.V Scott M.P Hedgehog and patched in neural development and disease.Neuron. 1998; 21: 1243-1257Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). Engineered mutations in Shh in mice show a remarkably similar holoprosencephalic phenotype in homozygotes (17Chiang C Litingtung Y Lee E Young K.E Corden J.L Westphal H Beachy P.A Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.Nature. 1996; 383: 407-413Crossref PubMed Scopus (2557) Google Scholar), though unlike the human phenotypes there is no heterozygote phenotype in mice. Other HPE genes are likely to be involved in SHH signaling, and preliminary evidence suggests that one such gene is PATCHED, which encodes a likely receptor and downstream target for SHH protein (Ming et al., 1998, Am. J. Hum. Genet., abstract). SHH protein requires cholesterol esterification to have normal activity. An animal toxin that interferes with this steroid modification causes HPE in animals (39Golden J.A Holoprosencephaly a defect in brain patterning.J. Neuropathol. Exp. Neurol. 1998; 57: 991-999Crossref PubMed Scopus (91) Google Scholar). Moreover, at least one other human disorder of cholesterol metabolism, the Smith-Lemli-Optiz syndrome, is associated with HPE (62Kelley R.L Roessler E Hennekam R.C Feldman G.L Kosaki K Jones M.C Palumbos J.C Muenke M Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome does abnormal cholesterol metabolism affect the function of Sonic Hedgehog?.Am. J. Med. Genet. 1996; 66: 478-484Crossref PubMed Scopus (185) Google Scholar) and has been postulated to interfere with the steroid modification required for normal SHH signaling. Whereas the known properties of SHH made it an obvious candidate gene for HPE, genetics offers the advantage of allowing one to identify unexpected genes with the same phenotype. A second HPE locus on chromosome 13q32 has recently been shown to reflect mutations in ZIC2, a human homolog of the Drosophila odd-paired gene (12Brown S.A Warburton D Brown L.Y Yu C.Y Roeder E.R Stengel-Rutkowski S Hennekam R.C Muenke M Holoprosencephaly due to mutations in ZIC2, a homolog of Drosophila odd-paired.Nat. Genet. 1998; 20: 180-183Crossref PubMed Scopus (396) Google Scholar) that encodes a homeodomain-containing transcription factor. ZIC2 is preferentially expressed in the dorsal region of the neural tube and in the developing extremity and defines the fates of neural cells in cooperation with the transcription factor Gli3 (12Brown S.A Warburton D Brown L.Y Yu C.Y Roeder E.R Stengel-Rutkowski S Hennekam R.C Muenke M Holoprosencephaly due to mutations in ZIC2, a homolog of Drosophila odd-paired.Nat. Genet. 1998; 20: 180-183Crossref PubMed Scopus (396) Google Scholar). Thus, although it can be imagined that ZIC2 operates somewhere downstream of SHH, it certainly provides a new entry point into the molecular specification of the forebrain. Other HPE genes will likely produce additional surprises: there are preliminary reports of two additional HPE genes—the transcription factors SIX3 and TGIF—that are not known to be targets of SHH (Gripp et al., 1998, Am. J. Hum. Genet., abstract; Wallis et al., 1998, Am. J. Hum. Genet., abstract). The division of the cerebral hemispheres along the dorsal midline is a complicated process about which little is known. Members of the bone morphogenetic protein (BMP) superfamily are critical for dorsal specification in other regions of the neuraxis (56Hogan B.L Bone morphogenetic proteins in development.Curr. Opin. Genet. Dev. 1996; 6: 432-438Crossref PubMed Scopus (662) Google Scholar, 68Liem Jr., K.F Tremml G Jessell T.M A role for the roof plate and its resident TGFβ-related proteins in neuronal patterning in the dorsal spinal cord.Cell. 1997; 91: 127-138Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar), and specific BMPs (e.g., BMP4 and BMP6) are expressed at high levels in the dorsal forebrain (34Furuta Y Piston D.W Hogan B.L Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development.Development. 1997; 124: 2203-2212Crossref PubMed Google Scholar), among the dorsal cells that invaginate along the dorsal midline to separate the hemispheres. The cells of the dorsal midline of the forebrain invaginate ventrally, separating the hemispheres, and then invaginate laterally into the medial walls of the two hemispheres to form the choroid plexus, a specialized vascular structure within the adult lateral ventricles that secretes the cerebral spinal fluid. Thus, these midline cells undergo widespread migration, rearrangement, and repression of neural fates, and BMPs seem to be likely candidates to mediate many of these effects, given their known roles in dorsal patterning and the repression of neural differentiation. It is somewhat paradoxical about HPE that the defects in ventral specification that produce the midline defects and cyclopia also result in a failure of the dorsal invagination and separation of the two cerebral hemispheres. Perhaps ZIC2 is especially important to this dorsal invagination. Schizencephaly represents a cleft, unilateral or bilateral, extending from the pial surface of the cortex all the way to the ventricular surface (4Barkovich A.J Kjos B.O Schizencephaly correlation of clinical findings with MR characteristics.AJNR Am. J. Neuroradiol. 1992; 13 (b): 85-94PubMed Google Scholar). The term is used more commonly in the radiographic literature, while neuropathologists prefer the term porencephaly, to refer to essentially an absence of cortex where cortex belongs (32Friede R.L Developmental Neuropathology. Springer-Verlag, Berlin1975Crossref Google Scholar). Typically, the sides of the cleft are lined with cortex that contains numerous small gyri, or “polymicrogyria” (Figure 2A and Figure 2B). Schizencephaly/porencephaly is quite variable and is undoubtedly causally heterogeneous. Some cases show an otherwise fairly normal cortex and mild clinical symptoms (usually seizures or cognitive difficulties). In other cases, there is a generalized malformation of the cortex accompanied by severe mental retardation and seizures (4Barkovich A.J Kjos B.O Schizencephaly correlation of clinical findings with MR characteristics.AJNR Am. J. Neuroradiol. 1992; 13 (b): 85-94PubMed Google Scholar). Schizencephaly was classically regarded as a vascular condition, perhaps reflecting in utero vascular insufficiency (4Barkovich A.J Kjos B.O Schizencephaly correlation of clinical findings with MR characteristics.AJNR Am. J. Neuroradiol. 1992; 13 (b): 85-94PubMed Google Scholar), and there is very convincing evidence for a vascular cause of some cases of schizencephaly (32Friede R.L Developmental Neuropathology. Springer-Verlag, Berlin1975Crossref Google Scholar). However, the first identification of mutations in the EMX2 gene in humans with clinically severe schizencephaly brought a surprise (14Brunelli S Faiella A Capra V Nigro V Simeone A Cama A Boncinelli E Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly.Nat. Genet. 1996; 12: 94-96Crossref PubMed Scopus (271) Google Scholar). EMX2 is a human homolog of the fly gene empty spiracles, which encodes a homeodomain-containing protein that is preferentially expressed in the developing cerebral cortex and is required for normal development of the cortex in mice (80Pellegrini M Mansouri A Simeone A Boncinelli E Gruss P Dentate gyrus formation requires Emx2.Development. 1996; 122: 3893-3898PubMed Google Scholar). Since EMX2 mutations are not seen in most cases of schizencephaly, it is not known whether other genes expressed in cortical or vascular progenitor cells also cause schizencephaly, or whether nongenetic vascular mechanisms account for other cases of schizencephaly. The term tuberous sclerosis (TSC) was coined to describe lesions of the brain that somehow resembled potato tubers in their gross consistency (Figure 3A). Tuberous sclerosis is a dominantly inherited multiorgan disorder with a high rate of spontaneous mutations. Tumors, cysts, and other malformations (called hamartomas) occur in many tissues, including kidney, bone, skin, and heart (65Kwiatkowski D.J Short M.P Tuberous sclerosis.Arch. Dermatol. 1994; 130: 348-354Crossref PubMed Scopus (156) Google Scholar). In the brain, there are two striking malformations. In the cortical gray matter, there are “cortical tubers,” otherwise called focal dysplasias (Figure 3A), in which the normal six-layered cortex is thickened and disordered (“dysplastic”), characterized by very large, filament-rich neurons and bizarre, enlarged glia-like cells. The dysplasias also contain giant cells referred to as “balloon cells” that stain for both neuronal and glial markers and that seem to be of uncertain lineage (94Vinters H.V Fisher R.S Cornford M.E Mah V Secor D.L De Rosa M.J Comair Y.G Peacock W.J Shields W.D Morphological substrates of infantile spasms studies based on surgically resected cerebral tissue.Childs Nerv. Syst. 1992; 8: 8-17Crossref PubMed Scopus (120) Google Scholar). Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules (Figure 3B) or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas (65Kwiatkowski D.J Short M.P Tuberous sclerosis.Arch. Dermatol. 1994; 130: 348-354Crossref PubMed Scopus (156) Google Scholar). The tuberous sclerosis hamartomas and tumors outside of the nervous system appear to arise through a tumor suppresser gene model, with the lesions reflecting inheritance of a germ-line TSC mutation from one parent, combined with the spontaneous loss of the second TSC allele in the clonal cells of each lesion (43Green A.J Smith M Yates J.R Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients.Nat. Genet. 1994; 6: 193-196Crossref PubMed Scopus (329) Google Scholar, 51Henske E.P Neumann H.P Scheithauer B.W Herbst E.W Short M.P Kwiatkowski D.J Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band 16p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas.Genes Chromosomes Cancer. 1995; 13: 295-298Crossref PubMed Scopus (223) Google Scholar). However, while the same “two-hit” mechanism, which was first developed by Knudson for retinoblastoma, appears to hold for the subependymal astrocytomas of the brain, there is no evidence for loss of both TSC alleles in tubers or subependymal nodules either in human tuberous sclerosis (52Henske E.P Scheithauer B.W Short M.P Wollmann R Nahmias J Hornigold N van Slegtenhorst M Welsh C.T Kwiatkowski D.J Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions.Am. J. Hum. Genet. 1996; 59: 400-406PubMed Google Scholar, 97Wolf H.K Normann S Green A.J von Bakel I Blumcke I Pietsch T Wiestler O.D von Deimling A Tuberous sclerosis-like lesions in epileptogenic human neocortex lack allelic loss at the TSC1 and TSC2 regions.Acta Neuropathol. (Berl.). 1997; 93: 93-96Crossref PubMed Scopus (27) Google Scholar) or in the Eker rat, which carries a spontaneous mutation in the TSC2 gene (101Yeung R.S Katsetos C.D Klein-Szanto A Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis.Am. J. Pathol. 1997; 151: 1477-1486PubMed Google Scholar). Presumably, the brain malformations represent some sort of second event after inheritance of a germline TSC mutation, but the type of second event that occurs is still not certain. A very similar clinical and anatomical picture of tuberous sclerosis is caused by mutations in two different, nonlinked genes, and both of them have now been cloned. The TSC2 gene was cloned some years ago, though its function is still not completely understood (26European Chromosome 16 Tuberous Sclerosis Consortium Identification and characterization of the tuberous sclerosis gene on chromosome 16.Cell. 1993; 75: 1305-1315Abstract Full Text PDF PubMed Scopus (1508) Google Scholar). The TSC2 gene encodes a widely expressed protein called tuberin, which contains a domain that has GAP activity for Rap1, a small G protein that relays membrane signals to the MAP kinase pathway (96Wienecke R Konig A DeClue J.E Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity.J. Biol. Chem. 1995; 270: 16409-16414Crossref PubMed Scopus (349) Google Scholar). Tuberin has also been implicated as a GAP for Rab5 (100Xiao G.H Shoarinejad F Jin F Golemis E.A Yeung R.S The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis.J. Biol. Chem. 1997; 272: 6097-6100Crossref PubMed Scopus (321) Google Scholar) and as a potential transcriptional coregulator (50Henry K.W Yuan X Koszewski N.J Onda H Kwiatkowski D.J Noonan D.J Tuberous sclerosis gene 2 product modulates transcription mediated by steroid hormone receptor family members.J. Biol. Chem. 1998; 273: 20535-20539Crossref PubMed Scopus (117) Google Scholar). The defects in cell type specification that characterize tuberous sclerosis lesions, as well as the tendency of some tuberous sclerosis lesions to transform into tumors, potentially implicates tuberin in regulating cell proliferation or cell fate specification, though very little is known about how tuberin might do this. Very recently, a fairly close TSC2 homolog in flies, encoded by the gigas gene, has been identified (60Ito N Rubin G gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle.Cell. 1999; 96: 529-539Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). In gigas mutant flies, cells undergo DNA replication in the absence of mitosis, forming giant, multiploid cells and disturbing the normal morphogenesis of the retina. The giant neural cells in tuberous sclerosis dysplasias have been suggested to represent similar multiploid cells due to defective cell cycle replication (60Ito N Rubin G gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle.Cell. 1999; 96: 529-539Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). The TSC1 gene on chromosome 9 causes a clinically very similar condition, but encodes a large novel protein, called hamartin, whose function is even less well understood (93van Slegtenhorst M de Hoogt R Hermans C Nellist M Janssen B Verhoef S Lindhout D van den Ouweland A Halley D Young J et al.Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.Science. 1997; 277: 805-808Crossref PubMed Scopus (1392) Google Scholar) but for which a good fly homolog also exists (60Ito N Rubin G gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle.Cell. 1999; 96: 529-539Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). Focal cortical dysplasias (FCDs) are actually encountered more frequently as single lesions in individuals with no other signs or symptoms of tuberous sclerosis than in the setting of tuberous sclerosis. The sporadic FCDs show a range of pathologies, but many closely resemble tuberous sclerosis lesions, leading to the suggestion by Andermann that they represent a “forme fruste” of tuberous sclerosis (1Andermann F Olivier A Melanson D Robitaille Y Epilepsy due to focal cortical dysplasia with macrogyria and the forme fruste of tuberous sclerosis a study of fifteen patients.Adv. Epilepsy. 1987; 16: 35-38Google Scholar). Sporadic FCDs may reflect one or more spontaneous mutations at the TSC and/or other loci, especially since the TSC genes are large and subject to high rates of spontaneous mutation; however, this suggestion is unproven. For mice, neuronal migration defects can only be demonstrated by studying neurogenesis and migration directly, and hence the term is used loosely when applied to human diseases where the same level of analysis is not possible. The best-characterized mouse neuronal migration disorders are the reeler (15Caviness Jr., V.S Sidman R.L Time of origin or corresponding cell classes in the cerebral cortex of normal and reeler mutant mice an autoradiographic analysis.J. Comp. Neurol. 1973; 148: 141-151Crossref PubMed Scopus (353) Google Scholar) and mdab1 (40Gonzalez J Russo C Goldowitz D Sweet H Davisson M Walsh C Birthdate and cell marker analysis of scrambler a novel mutation affecting cortical development with a reeler-like phenotype.J. Neurosci. 1997; 17: 9204-9211PubMed Google Scholar, 58Howell B Hawkes R Soriano R Cooper J Neuronal position in the developing brain is regulated by mouse disabled-1.Nature. 1997; 389: 733-737Crossref PubMed Scopus (619) Google Scholar, 90Sheldon M Rice D D’Arcangelo G Yoneshima H Nakajima K Mikoshiba K Howell B Cooper J Goldowitz D Curran T scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice.Nature. 1997; 389: 730-733Crossref PubMed Scopus (556) Google Scholar, 95Ware M Fox J Gonzalez J Davis N Lambert de Rouvroit C Chua S Goffinet A Walsh C Aberrant splicing of a mouse disabled homolog, mdab1, in the scrambler mouse.Neuron. 1997; 19: 239-249Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar) mutants, and the engineered mutations in cdk-5 (78Ohshima T Ward J Huh C Longenecker G Veeranna Pant H Brady R Martin L Kulkarni A Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death.Proc. Natl. Acad. Sci. USA. 1996; 93: 11173-11178Crossref PubMed Scopus (808) Google Scholar, 37Gilmore E.C Ohshima T Goffinet A.M Kulkarni A.B Herrup K Cyclin-dependent kinase 5–deficient mice demonstrate novel developmental arrest in cerebral cortex.J. Neurosci. 1998; 18: 6370-6377Crossref PubMed Google Scholar) and its regulator, p35 (16Chae T Kwon Y Bronson R Dikkes P Li E Tsai L Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality.Neuron. 1997; 18: 29-42Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar). There are, however, a large group of human disorders that are most consistent with disorders of migration, and they frequently present radiographically with associated disorders of the gyral pattern of the cortex. Lissencephaly, meaning literally “smooth brain,” refers to a genetically, clinically, radiographically, and histologically heterogeneous group of conditions that all are manifested radiographically by a simplification or complete loss of the gyri and sulci that characterize the normal human brain (Figure 2C). Agyria (“no gyri”), a related term, is used roughly synonymously, whereas pachygyria refers to gyri that are both reduced in number and unusually thick, often ten times thicker than normal, producing a cortex that is quite small in surface area but not obviously reduced in neuronal numbers. The abnormalities of gyration appear to be a secondary and nonspecific consequence of widespread cortical malformation and are easily apparent radiographically (Figure 2C). Although the gyral pattern is frequently used as a marker for the migrational disturbance, the relationship is quite imprecise. There are at least two relatively common and distinct histological patterns of lissencephaly: “classical” lissencephaly, also known as Type I or Bielschowsky type; and “cobblestone” lissencephaly, also known as Type II. However, there are probably additional histological patterns associated with lissencephaly that are not as well characterized. The most common genetic cause of classical lissencephaly is gross disruption of a gene on chromosome 17p13 called LIS1, or more properly PAFAH1B1 (85Reiner O Carrozzo R Shen Y Wehnert M Faustinella F Dobyns W.B Caskey C.T Ledbetter D.H Isolation of a Miller-Dieker lissencephaly gene containing G protein β-subunit-like repeats.Nature. 1993; 364: 717-721Crossref PubMed Scopus (909) Google Scholar). PAFAH1B1 mutations cause a range of severity of lissencephaly referred to as the “isolated lissencephaly sequence” (24Dobyns W.B Reiner O Carrozzo R Ledbetter D.H Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13.J. Am. Med. Assoc. 1993; 270: 2838-2842Crossref PubMed Scopus" @default.
• W2038567507 created "2016-06-24" @default.
• W2038567507 creator A5009957197 @default.
• W2038567507 date "1999-05-01" @default.
• W2038567507 modified "2023-10-13" @default.
• W2038567507 title "Genetic Malformations of the Human Cerebral Cortex" @default.
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