Nature Genetics
27, 117 - 120 (2001)
doi:10.1038/83679
Mutations in GFAP, encoding glial fibrillary acidic protein, are
associated with Alexander diseaseMichael Brenner1, Anne B. Johnson2, Odile Boespflug-Tanguy3, Diana Rodriguez4, James E. Goldman5
& Albee Messing61
Departments of Neurobiology, and Physical Medicine
and Rehabilitation, University of Alabama-Birmingham, Birmingham
, Alabama, USA. 2
Departments of Pathology and Neuroscience, Albert Einstein
College of Medicine, Bronx, New York, USA.
3
Inserm U.384, Faculte de Medecine, Clermont-Ferrand
, France. 4
Service de Neuropédiatrie, Hôpital Saint
Vincent de Paul, AP-HP, Paris, France. 5
Department of Pathology and Center for Neurobiology
and Behavior, Columbia University College of Physicians & Surgeons,
New York, New York, USA. 6
Department of Pathobiological Sciences, Waisman Center
and School of Veterinary Medicine, University of Wisconsin, Madison
, Wisconsin, USA.
Correspondence should be addressed to Albee Messing messing@waisman.wisc.eduAlexander 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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