Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly. - Université de Rennes Accéder directement au contenu
Article Dans Une Revue American Journal of Human Genetics Année : 2012

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

Céline Bouchet-Séraphin
  • Fonction : Auteur
Malika Chelbi
  • Fonction : Auteur
Anne Bazin
  • Fonction : Auteur
Fabien Guimiot
  • Fonction : Auteur
  • PersonId : 841588
Christine Bole-Feysot
  • Fonction : Auteur
Jean-Pierre Bernard
  • Fonction : Auteur
Koryna Socha
  • Fonction : Auteur
Bernard Grandchamp
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-01120423 , version 1 (25-02-2015)

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Citer

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, 2012, 91 (6), pp.1135-43. ⟨10.1016/j.ajhg.2012.10.009⟩. ⟨hal-01120423⟩
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