Infantile Alexander Disease: Spectrum of GFAP Mutations and Genotype-Phenotype Correlation Diana Rodriguez, Fernande Gauthier, Enrico Bertini, Marianna.

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Infantile Alexander Disease: Spectrum of GFAP Mutations and Genotype-Phenotype Correlation Diana Rodriguez, Fernande Gauthier, Enrico Bertini, Marianna Bugiani, Michael Brenner, Sylvie N'guyen, Cyril Goizet, Antoinette Gelot, Robert Surtees, Jean-Michel Pedespan, Xavier Hernandorena, Monica Troncoso, Graziela Uziel, Albee Messing, Gérard Ponsot, Danielle Pham-Dinh, André Dautigny, Odile Boespflug-Tanguy The American Journal of Human Genetics Volume 69, Issue 5, Pages 1134-1140 (November 2001) DOI: 10.1086/323799 Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 1 A and B, Typical T2-weighted MRI images of brains of patients with infantile Alexander disease. A, Classical form (patient 7). B, Mild form (patient 3). Note that both patients show the high signal intensity of white matter, predominately in the frontal area, and of the basal ganglia. C, Rosenthal fiber in Alexander disease viewed by electron microscopy (patient 15); original magnification ×28,500. The American Journal of Human Genetics 2001 69, 1134-1140DOI: (10.1086/323799) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 2 A, Identification of novel mutations in the GFAP gene in four patients with Alexander disease. Segments of the sequencing chromatograms in the region of each mutated nucleotide are shown, with the site of the heterozygous point mutation indicated by an arrow. B, Confirmation of the heterozygous 240C→T point mutation by RFLP analysis. This point mutation results in the loss of a restriction site for SacI. Digestion of a PCR-amplified fragment of genomic DNA from control subjects produced three fragments of 368, 280, and 39 bp (C1 and C2). RFLP analysis of the affected individual generated four fragments of 648, 368, 280, and 39 bp; the 648-bp fragment (368 bp + 280 bp) arose from loss of the SacI site on one of the chromosomes (case 1). The 39-bp restriction fragment is not shown in this gel. ND = nondigested PCR-amplified fragment. C, Schematic representation of the GFAP gene and the corresponding protein, showing the localization of mutations in Alexander disease. The nine exons of the GFAP gene are represented by boxes, and introns are represented by lines. Multiple occurrences of a mutation are indicated by the number shown in parentheses, and mutations described elsewhere (Brenner et al. 2001) are shown in blue. Mutations are clustered within exons encoding the rod domain of GFAP. The American Journal of Human Genetics 2001 69, 1134-1140DOI: (10.1086/323799) Copyright © 2001 The American Society of Human Genetics Terms and Conditions