Document Detail

Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly.
MedLine Citation:
PMID:  23217329     Owner:  NLM     Status:  MEDLINE    
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.
Sandrine Vuillaumier-Barrot; Céline Bouchet-Séraphin; Malika Chelbi; Louise Devisme; Samuel Quentin; Steven Gazal; Annie Laquerrière; Catherine Fallet-Bianco; Philippe Loget; Sylvie Odent; Dominique Carles; Anne Bazin; Jacqueline Aziza; Alix Clemenson; Fabien Guimiot; Maryse Bonnière; Sophie Monnot; Christine Bole-Feysot; Jean-Pierre Bernard; Laurence Loeuillet; Marie Gonzales; Koryna Socha; Bernard Grandchamp; Tania Attié-Bitach; Férechté Encha-Razavi; Nathalie Seta
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of human genetics     Volume:  91     ISSN:  1537-6605     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-10     Completed Date:  2013-02-14     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1135-43     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Biochimie, Paris 75877, France.
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MeSH Terms
Cobblestone Lissencephaly / diagnosis,  genetics*
Fetus / metabolism,  pathology
Gene Order
Membrane Proteins / genetics*
Nucleotidyltransferases / genetics*
Reg. No./Substance:
0/Membrane Proteins; 0/TMEM5 protein, human; EC 2.7.7.-/ISPD protein, human; EC 2.7.7.-/Nucleotidyltransferases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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