Location and type of mutation in the
            <i>LIS1</i>
            gene do not predict phenotypic severity

Uyanık, G.; Morris-Rosendahl, Deborah J.; Stiegler, J.; Klapecki, Jakub; Groß, Claudia; Berman, Yemima; Martin, Peter; Dey, Lara-Sophie; Spranger, Stephanie; Korenke, G. C.; Schreyer, Isolde; Hertzberg, Christoph; Neumann, Thomas; Burkart, P.; Spaich, Christiane; Meng, Mingyao; Holthausen, Hans; Adès, Lesley C.; Seidel, Joerg; Mangold, Elisabeth; Buyse, Gunnar; Meinecke, Peter; Schara, Ulrike; Zeschnigk, Christine; Müller, Dietmar; Helland, G.; Schulze, Bernd; Wright, MJ; Körtge-Jung, Stefani; Hehr, Andreas; Bogdahn, Ulrich; Schuierer, Gerhard; Kohlhase, Jürgen; Aigner, Ludwig; Wolff, Gerhard; Hehr, Ute; Winkler, Jürgen

doi:10.1212/01.wnl.0000266629.98503.d0

Cited by 41 publications

(57 citation statements)

References 27 publications

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“…Although mostly attributed to mutations in PAFAH1B1, RELN, VLDLR and TUBA1A, the underlying genetic defects in some patients with LCH still remains unknown (Hong et al 2000;Uyanik et al 2007;Kumar et al 2010;Friocourt et al 2011).…”

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confidence: 99%

Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5

et al. 2015

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Lissencephaly comprises a heterogeneous group of developmental brain disorders of varying severity, involving abnormal cortical gyration. We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Using microarray-based homozygosity mapping in the reported family, combined with whole exome sequencing in one affected infant, we identified a homozygous splice site mutation g.IVS8+1G>A in cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162SfsX19). The mutation co-segregated with the disease phenotype in all 29 study participants (4 patients and 25 healthy relatives), and was not identified in 200 ethnically matched control chromosomes. The p.V162SfsX19 mutation causes lack of endogenous CDK5 expression in affected dermal fibroblasts and brain tissue at the mRNA and protein levels, consistent with nonsense-mediated mRNA decay. Functional analysis of the p.V162SfsX19 mutation, using a yeast complementation assay, showed loss-of-function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family.

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confidence: 99%

Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5

et al. 2015

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“…Mutations of LIS1 (including deletions), DCX and TUBA1A account for 65%, 12% and an unknown but small percent of patients with lissencephaly. In contrast to previous reports, recent data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity (29). The proteins coded by these genes all regulate microtubule and cytoplasmic dynein function and -at least for LIS1 -interfere with neuronal migration by blocking microtubule-directed nuclear movement in VZ neuroblasts, conversion of nascent post-mitotic neurons to multipolar pre-migratory cells and conversion of multipolar to bipolar migratory cells.…”

Section: Genetics In Lissencephalymentioning

confidence: 63%

Neuronal migration disorders: clinical, neuroradiologic and genetics aspects

et al. 2009

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Disorders of neuronal migration are a heterogeneous group of disorders of nervous system development. One of the most frequent disorders is lissencephaly, characterized by a paucity of normal gyri and sulci resulting in a 'smooth brain'. There are two pathologic subtypes: classical and cobblestone. Six different genes could be responsible for this entity (LIS1, DCX, TUBA1A, VLDLR, ARX, RELN), although co-delection of YWHAE gene with LIS1 could result in Miller-Dieker Syndrome. Heterotopia is defined as a cluster of normal neurons in abnormal locations, and divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia. Genetically, heterotopia is related to Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2) genes mutations. Polymicrogyria is described as an augmentation of small circonvolutions separated by shallow enlarged sulci; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria results in a clinical syndrome manifested by mild mental retardation, epilepsy and pseudobulbar palsy. Gene mutations linked to this disorder are SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1. Schizencephaly, consisting in a cleft of cerebral hemisphere connecting extra-axial subaracnoid spaces and ventricles, is another important disorder of neuronal migration whose clinical characteristics are extremely variable. EMX2 gene could be implicated in its genesis. Focal cortical dysplasia is characterized by three different types of altered cortical laminations, and represents one of most severe cause of epilepsy in children. TSC1 gene could play a role in its etiology. Conclusion: This review reports the main clinical, genetical and neuroradiological aspects of these disorders. It is hoped that accumulating data of the development mechanisms underlying the expanded network formation in the brain will lead to the development of therapeutic options for neuronal migration disorders.

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“…4 The degree of agyria in lissencephaly may vary and has been stratified by Dobyns into six different grades of severity. 1,5 Grade 1, as occurred in this patient, is complete agyria. Grade 2 has some minimal gyration in the frontal region.…”

Section: Denouement and Discussionmentioning

confidence: 54%

Miller–Dieker syndrome, type 1 lissencephaly

Herman

Siegel

2008

J Perinatol

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Case presentation A 1910 g infant was born at 41-weeks gestation to a 19-year-old gravida 1 mother after a pregnancy complicated by hydramnios and poor fetal movement. The child was delivered by a cesarean section because of fetal decelerations with labor. Severe intrauterine growth retardation was present with the infant's weight, length and head circumference all less than the tenth percentile for gestational age. The patient's head demonstrated a wasted appearance with bitemporal shallowness. The ears were low set. Retromicrognathia, and microphthalmia, more marked on the left, were also present. The child had a cranial sonogram (Figure 1) and cranial magnetic resonance imaging (Figure 2). Denouement and discussionThe cranial sonogram demonstrated an abnormally smooth brain with no gyration or sulcation with a wide, shallow sylvian fissure creating a figure-of-8 appearance. The absence of all gyri is

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Location and type of mutation in the LIS1 gene do not predict phenotypic severity

Cited by 41 publications

References 27 publications

Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5

Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5

Neuronal migration disorders: clinical, neuroradiologic and genetics aspects

Miller–Dieker syndrome, type 1 lissencephaly

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