Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease


Alexander disease is a rare disorder of the central nervous system of unknown etiology1,2. Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation, leading to death usually within the first decade; patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. The pathological hallmark of all forms of Alexander disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins3,4. We previously found that overexpression of human GFAP in astrocytes of transgenic mice is fatal and accompanied by the presence of inclusion bodies indistinguishable from human Rosenthal fibers5. These results suggested that a primary alteration in GFAP may be responsible for Alexander disease. Sequence analysis of DNA samples from patients representing different Alexander disease phenotypes revealed that most cases are associated with non-conservative mutations in the coding region of GFAP. Alexander disease therefore represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate CNS.

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Figure 1: GFAP mutations in Alexander disease patients characterized by DNA sequencing.
Figure 2: Detection of mutations by restriction endonuclease digestion.
Figure 3: Location of mutations in GFAP associated with Alexander disease in relation to protein domain structure of intermediate filaments.


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We thank the Brain and Tissue Bank for Developmental Disorders at the University of Maryland (supported by NIH), the National Neurological Specimen Bank, and the Laboratorio di Diagnosi Pre e Postnatale delle Malattie Metaboliche (Instituto G. Gaslini; supported by Telethon project C.20) for samples of Alexander disease tissues from their collections; A. Koeppen and M. Mahadevan for control samples; the AECOM Human Genetics Program and J. Cowell for helping to prepare some of the samples; D. Klimanis, J. Salmon and Y. Yang for processing samples and data analysis; J. Nagle and S. Hollingshead for sequencing; L. Harman for paternity testing; R. Spritz and M. Hutton for advice; the families of Alexander disease patients for encouragement and assistance; and the United Leukodystrophy Foundation for support. The UAB sequencing facility is partially supported by grants from the Tennessee Valley Authority and the Howard Hughes Foundation. During the early stages of this work, M.B. was supported at the NIH by the NINDS intramural program through J.M. Hallenbeck. This project was supported by NIH grants NS-22475 (A.M.) and EY-09331 (J.E.G.), by the Lie Endowment (M.B.), and by the Institut National de la Santé et de la Recherche Médicale, the European Leukodystrophies Association (ELA France), the Biomed 2 EC project and the Jean Pierre and Nancy Boespflug Foundation for Myopathic Research (O.B.-T. and D.R.).

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Correspondence to Albee Messing.

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Brenner, M., Johnson, A., Boespflug-Tanguy, O. et al. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27, 117–120 (2001) doi:10.1038/83679

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