Clin Genet 2007 Printed in Singapore. All rights reserved # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaard CLINICAL GENETICS doi: 10.1111/j.1399-0004.2007.00869.x Short Report GFAP mutations and polymorphisms in 13 unrelated Italian patients affected by Alexander disease Caroli F, Biancheri R, Seri M, Rossi A, Pessagno A, Bugiani M, Corsolini F, Savasta S, Romano S, Antonelli C, Romano A, Pareyson D, Gambero P, Uziel G, Ravazzolo R, Ceccherini I, Filocamo M. GFAP mutations and polymorphisms in 13 unrelated Italian patients affected by Alexander disease. Clin Genet 2007. # Blackwell Munksgaard, 2007 Alexander disease (AD), a rare neurodegenerative disorder of the central nervous system, is characterized by the accumulation of cytoplasmic protein aggregates (Rosenthal fibers) composed of glial fibrillary acidic protein (GFAP) and small heat-shock proteins within astrocytes. To date, more than 40 different GFAP mutations have been reported in AD. The present study is aimed at the molecular diagnosis of Italian patients suspected to be affected by AD. By analyzing the GFAP gene of 13 unrelated patients (eight with infantile form, two with juvenile form and three with adult form), we found 11 different alleles, including four new ones. Among the novel mutations, three (p.R70Q, p.R73K, and p.R79P) were identified in exon 1 and p.L359P in exon 6. The sequence analysis also detected six different single nucleotide polymorphic variants, including two previously unreported ones, spread throughout non-coding regions (introns 2, 3, 5, 6, and 3#UTR) of the gene. All patients were heterozygous for the mutations, thus confirming their dominant effect. F Caroli a, *, R Biancheri b, *, M Seri c , A Rossi d , A Pessagno e , M Bugiani f , F Corsolini g , S Savasta h , S Romano i , C Antonelli j , A Romano k , D Pareyson l , P Gambero m , G Uziel f , R Ravazzolo a , I Ceccherini a and M Filocamo g a Laboratory of Molecular Genetics, and b Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute, Genoa, Italy, c Laboratory of Medical Genetics, University of Bologna, Bologna, Italy, d Department of Pediatric Neuroradiology, and e U.O. Neuropsichiatria Infantile, G. Gaslini Institute, Genoa, Italy, f Department of Child Neurology, C. Besta Institute, Milan, Italy, g Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, G. Gaslini Institute, Genoa, Italy, h Department of Pediatrics, S. Matteo Hospital, Pavia, Italy, i Department of Neurology, Sant’Andrea Hospital, Rome, Italy, j Neuropsichiatria Infantile, AOU Careggi, Florence, Italy, k Department of Pediatrics, Federico II, University of Naples, Naples, Italy, l Department of Biochemistry and Genetics, C. Besta Institute, Milan, Italy, and m Clinica Neurologica, L. Sacco Hospital, Milan, Italy *These authors contributed equally to this study. Key words: Alexander disease – GFAP – leukoencephalopathy – MRI – mutations – neurodegenerative disorder – SNPs Corresponding author: Mirella Filocamo, Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, L.go G. Gaslini, 16147 Genova, Italy. Tel.: 139 010 5636 792; fax: 139 010 383983; e-mail: mirellafilocamo@ospedale-gaslini. ge.it Received 3 April 2007, revised and accepted for publication 30 May 2007 1