Hong, S. E. et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nature Genet. 26, 93-96

Division of Neurogenetics, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.65). 10/2000; 26(1):93-6. DOI: 10.1038/79246
Source: PubMed

ABSTRACT Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Two identified lissencephaly genes do not account for all known cases, and additional lissencephaly syndromes have been described. An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN). The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity. RELN encodes a large (388 kD) secreted protein that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11 ), alpha3beta1 integrin and protocadherins. Although reelin was previously thought to function exclusively in brain, some humans with RELN mutations show abnormal neuromuscular connectivity and congenital lymphoedema, suggesting previously unsuspected functions for reelin in and outside of the brain.

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    • "ELN , VLDLR , and TUBA1A muta - tions [ Jissendi‐Tchofo et al . , 2009b ] . RELN ( OMIM 257320 ) encodes an extracellular matrix‐associated glyco - protein ( reelin ) that is secreted by Cajal – Retzius cells in the developing cerebral cortex . Reelin is critical for the regulation of neuronal migration during cortical and cerebellar development [ Hong et al . , 2000 ] . Affected children show severe developmental disabilities , microcephaly , seizures , and congenital lymphedema . Neuroimaging findings include pachygyria , severe CH with abnormal foliation and more severe involvement of the vermis compared to the hemispheric and pontine involvement . VLDLR ( OMIM 224050 ) encodes the very low‐densi"
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    ABSTRACT: Cerebellar hypoplasia (CH) refers to a cerebellum with a reduced volume, and is a common, but non-specific neuroimaging finding. The etiological spectrum of CH is wide and includes both primary (malformative) and secondary (disruptive) conditions. Primary conditions include chromosomal aberrations (e.g., trisomy 13 and 18), metabolic disorders (e.g., molybdenum cofactor deficiency, Smith-Lemli-Opitz syndrome, and adenylosuccinase deficiency), genetic syndromes (e.g., Ritscher-Schinzel, Joubert, and CHARGE syndromes), and brain malformations (primary posterior fossa malformations e.g., Dandy-Walker malformation, pontine tegmental cap dysplasia and rhombencephalosynapsis, or global brain malformations such as tubulinopathies and α-dystroglycanopathies). Secondary (disruptive) conditions include prenatal infections (e.g., cytomegalovirus), exposure to teratogens, and extreme prematurity. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling. Neuroimaging provides key information to categorize CH based on the pattern of involvement: unilateral CH, CH with mainly vermis involvement, global CH with involvement of both vermis and hemispheres, and pontocerebellar hypoplasia. The category of CH, associated neuroimaging findings and clinical features may suggest a specific disorder or help plan further investigations and interpret their results. Over the past decade, advances in neuroimaging and genetic testing have greatly improved clinical diagnosis, diagnostic testing, recurrence risk counseling, and information about prognosis for patients and their families. In the next decade, these advances will be translated into deeper understanding of these disorders and more specific treatments. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 06/2014; 166(2). DOI:10.1002/ajmg.c.31398 · 3.54 Impact Factor
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    • "followed by mutations in LIS1, a key gene involved in neuronal migration , in children with lissencephaly in 1983 changed our understanding of the etiology of human brain malformations [Dobyns et al., 1983]. The subsequent identification of mutations in DCX and RELN in children with other patterns of lissencephaly reinforced that mutations in genes associated with neuronal migration cause severe malformations of the forebrain [Pilz et al., 1998; Hong et al., 2000]. Since then, the accelerated rate of gene discovery, particularly with the introduction of next generation sequencing (NGS), has uncovered a large number of novel genes associated with malformations of cortical and cerebellar development (Table I) (Fig. 1). "
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    ABSTRACT: This issue of the American Journal of Medical Genetics Seminar Series Part C is dedicated to congenital brain malformations with a special focus on the molecular mechanisms underlying this fascinating, and often complex, group of developmental brain disorders. As with most genetic disorders, the past few years have witnessed a dramatic leap in our understanding of the molecular basis of these malformations that include both constitutional and post-zygotic (or mosaic) genetic aberrations. This is best exemplified by the recent identification of mutations within components of the PI3K-AKT-mTOR pathway in hemimegalencephaly and megalencephaly syndromes, and the rapidly increased identification of mutations within the tubulin family in a broad range of cortical and non-cortical brain malformations. These discoveries, particularly of the emerging “tubulinopathies” spectrum, have not only expanded our knowledge of these disorders but challenge our existing, and perhaps overly simplistic, classification of these malformations based on the primary neuronal stage at which the abnormality occurs. It is our hope that this series will facilitate a deeper understanding of these malformations beyond their clinical and neuroimaging features and syndromic associations to their molecular and pathway underpinnings. We believe this knowledge will most certainly be instrumental as we move into the era of delineating genotype-phenotype correlations and, ultimately, pathway-based therapies. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 06/2014; 166(2). DOI:10.1002/ajmg.c.31404 · 3.54 Impact Factor
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    • "This gene is known to regulate frontal cortex identity [Bedogni et al., 2010a], to be part of the PAX6–TBR2–NEUROD–TBR1 cascade that controls the glutamatergic neuronal cell fate [Méndez-Gó mez et al., 2011], and to have a role in the CASK–TBR1–RELN pathway important for neuronal migration [Hevner et al., 2006]. Mutations of these genes in humans have been associated with alterations in embryological brain development [Mitchell et al., 2003] and neuronal migration disorders [Hong et al., 2000]. Also, one of TBR1's targets is the AUTS2, whose altered expression has been documented in patients with autism and/or intellectual disabilities [Bedogni et al., 2010b; Nagamani et al., 2013]. "
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    ABSTRACT: Interstitial deletion of 2q24.2 is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Previously reported genotype-phenotype correlation identified a minimum deleted region of 2.65 Mb including 15 genes. Recently, a patient with a de novo 2q24.2 microdeletion of 0.4 Mb encompassing only three genes was described. However, the precise relationship between most deleted genes and the clinical features remains unclear. Here we describe a 12-year-old male patient diagnosed with growth retardation and ID. He also showed microcephaly, right palpebral ptosis, scapular winging, and pectus excavatum. Single nucleotide polymorphisms (SNP) array analysis showed a de novo interstitial deletion of 0.122 Mb at 2q24.2 region harboring only TBR1 (T-box, brain, 1; OMIM: 604616), which encodes a T-box family transcription factor expressed in post-mitotic projection neurons and functionally significant in embryologic corticogenesis. This is the first case of a deletion at 2q24.2 involving only TBR1. This finding narrows the smallest region of overlap (SRO) for deletions in this region and strengthens the previously suggested hypothesis that this gene is a strong candidate for the ID phenotype. The identification of TBR1 as candidate for ID encourages further molecular studies to identify novel mutations to understand the pathogenic effects of its haploinsufficiency. Finally, this report provides a review on 10 2q24.2 microdeletion patients. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2014; 164(3). DOI:10.1002/ajmg.a.36363 · 2.05 Impact Factor
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