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)

1 Unité UMR_S956
2 Pôle de Pathologie, Centre de Biologie Pathologie
3 Inserm U745 - Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux
4 Variabilité Génétique et Maladies Humaines
5 Service d'Anatomie et Cytologie Pathologique [CHU Rouen]
6 Néovasc - Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement
7 Département de pathologie et biologie cellulaire
8 Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes]
9 IGDR - Institut de Génétique et Développement de Rennes
10 Service de pathologie [Bordeaux]
11 Service Anatomie et cytologie pathologiques [CHU Toulouse]
12 LIDILEM - LInguistique et DIdactique des Langues Étrangères et Maternelles
13 Service de Biologie du Développement
14 CHU Necker - Enfants Malades [AP-HP]
15 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
16 Service de Génétique Médicale [CHU Necker]
17 Service d'Anatomie et de Cytologie Pathologiques
18 CHU Trousseau [APHP]
19 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
20 Service de Cytogénétique et Embryologie
21 Laboratoire de biochimie métabolique et cellulaire

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.

Domains: Life Sciences [q-bio]

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⟩