title: Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly.
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.
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Biochimie, Paris 75877, France. sandrine.vuillaumier@bch.aphp.fr
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vuillaumier-Barrot
authors.forename: Céline
authors.initials: C
authors.lastname: Bouchet-Séraphin
authors.forename: Malika
authors.initials: M
authors.lastname: Chelbi
authors.forename: Louise
authors.initials: L
authors.lastname: Devisme
authors.forename: Samuel
authors.initials: S
authors.lastname: Quentin
authors.forename: Steven
authors.initials: S
authors.lastname: Gazal
authors.forename: Annie
authors.initials: A
authors.lastname: Laquerrière
authors.forename: Catherine
authors.initials: C
authors.lastname: Fallet-Bianco
authors.forename: Philippe
authors.initials: P
authors.lastname: Loget
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Dominique
authors.initials: D
authors.lastname: Carles
authors.forename: Anne
authors.initials: A
authors.lastname: Bazin
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Aziza
authors.forename: Alix
authors.initials: A
authors.lastname: Clemenson
authors.forename: Fabien
authors.initials: F
authors.lastname: Guimiot
authors.forename: Maryse
authors.initials: M
authors.lastname: Bonnière
authors.forename: Sophie
authors.initials: S
authors.lastname: Monnot
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bernard
authors.forename: Laurence
authors.initials: L
authors.lastname: Loeuillet
authors.forename: Marie
authors.initials: M
authors.lastname: Gonzales
authors.forename: Koryna
authors.initials: K
authors.lastname: Socha
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.forename: Férechté
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Seta
mesh_terms: D000483:Alleles; D054222:Cobblestone Lissencephaly / Q000175:diagnosis / Q000235:genetics*; D003241:Consanguinity; D005091:Exons; D005190:Family; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D023061:Gene Order; D005838:Genotype; D006801:Humans; D007438:Introns; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009713:Nucleotidyltransferases / Q000235:genetics*; D010430:Pentosyltransferases
chemical_list: D008565:Membrane Proteins; D010430:Pentosyltransferases; C578283:RXYLT1 protein, human; D009713:Nucleotidyltransferases; C573136:CRPPA protein, human