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Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly.

Sandrine Vuillaumier-Barrot 1 Céline Bouchet-Séraphin Malika Chelbi Louise Devisme 2 Samuel Quentin 3 Steven Gazal 4 Annie Laquerrière 5, 6 Catherine Fallet-Bianco 7 Philippe Loget 8 Sylvie Odent 9 Dominique Carles 10 Anne Bazin Jacqueline Aziza 11 Alix Clemenson 12 Fabien Guimiot 13 Maryse Bonnière 14 Sophie Monnot 15, 16 Christine Bole-Feysot Jean-Pierre Bernard Laurence Loeuillet 17 Marie Gonzales 18 Koryna Socha Bernard Grandchamp Tania Attié-Bitach 16, 19 Férechté Encha-Razavi 20 Nathalie Seta 21
Abstract : Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the arachnoid space forms an extracortical layer that produces agyria and/or a "cobblestone" brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies.
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Submitted on : Wednesday, February 25, 2015 - 3:37:20 PM
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Sandrine Vuillaumier-Barrot, Céline Bouchet-Séraphin, Malika Chelbi, Louise Devisme, Samuel Quentin, et al.. Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly.. American Journal of Human Genetics, Elsevier (Cell Press), 2012, 91 (6), pp.1135-43. ⟨10.1016/j.ajhg.2012.10.009⟩. ⟨hal-01120423⟩



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