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Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype

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Abstract

Neuronal migration disorders account for a substantial number of cortical malformations, the most severe forms being represented by lissencephalies. Classical lissencephaly has been shown to result from mutations in LIS1 (PAFAH1B1; MIM#601545), DCX (Doublecortin; MIM#300121), ARX (Aristaless-related homeobox gene; MIM#300382), RELN (Reelin; MIM#600514) and VLDLR (Very low density lipoprotein receptor; MIM#224050). More recently, de novo missense mutations in the alpha-tubulin 1a gene (TUBA1A) located on chromosome 12q13.12, have also been associated with more or less severe defects of cortical development, resulting in complete agyria in the most severe cases of lissencephaly. We report here the cerebral lesions in a 36 weeks’ gestation female foetus with a novel de novo missense mutation in the TUBA1A gene, presenting the most severe antenatal phenotype reported so far. Using routine immunohistochemistry and confocal microscopy, we show evidence for defects in axonal transport in addition to defects in neuronal migration and differentiation, giving new insights to the pathophysiology of this form of lissencephaly.

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Acknowledgments

The authors wish to thank Philippe Bourgeois for his technical assistance, the plateform Primagen for confocal analysis techniques and Esther Le Roy for the iconography.

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Authors and Affiliations

  1. Faculty of Medicine, INSERM, U614, IFRMP23, Rouen Institute for Medical Research and Innovation, University of Rouen, Rouen, France

    Magalie Lecourtois & Pascale Saugier-Veber

  2. Cochin Institute, Paris-Descartes University, CNRS (UMR 8104), Paris, France

    Karine Poirier, Xavier Jaglin & Jamel Chelly

  3. INSERM, U567, Paris, France

    Karine Poirier & Jamel Chelly

  4. INSERM, U613, University of Brest, IFR148, Brest, France

    Gaëlle Friocourt

  5. Laboratory of Molecular Genetics and Histocompatibility, CHU Brest, Brest, France

    Gaëlle Friocourt

  6. Department of Medical Genetics, Rouen University Hospital, Rouen, France

    Alice Goldenberg & Pascale Saugier-Veber

  7. Pathology Laboratory, Rouen University Hospital, Rouen, France

    Annie Laquerrière

  8. Faculty of Medicine, EA 4309 Neovasc, Rouen Institute for Medical Research and Innovation, University of Rouen, Rouen, France

    Annie Laquerrière

  9. Pathology Laboratory-Pavillon Jacques Delarue, Hôpital Charles Nicolle, 1, rue de Germont, 76031, Rouen Cedex, France

    Annie Laquerrière

Authors
  1. Magalie Lecourtois
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  2. Karine Poirier
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  3. Gaëlle Friocourt
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  4. Xavier Jaglin
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  5. Alice Goldenberg
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  6. Pascale Saugier-Veber
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  7. Jamel Chelly
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  8. Annie Laquerrière
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Correspondence to Annie Laquerrière.

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Lecourtois, M., Poirier, K., Friocourt, G. et al. Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype. Acta Neuropathol 119, 779–789 (2010). https://doi.org/10.1007/s00401-010-0684-z

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  • DOI: https://doi.org/10.1007/s00401-010-0684-z

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