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

Nat Genet. 2001 Jan;27(1):117-20. doi: 10.1038/83679.

Abstract

Alexander disease is a rare disorder of the central nervous system of unknown etiology. 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 proteins. 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 fibers. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Age of Onset
  • Asian Continental Ancestry Group / genetics
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Base Sequence
  • Central Nervous System Diseases / genetics*
  • Central Nervous System Diseases / metabolism
  • Central Nervous System Diseases / pathology
  • Central Nervous System Diseases / physiopathology
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • DNA Restriction Enzymes / metabolism
  • Europe / ethnology
  • Female
  • Glial Fibrillary Acidic Protein / chemistry
  • Glial Fibrillary Acidic Protein / genetics*
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Polymerase Chain Reaction
  • Psychomotor Disorders / genetics
  • Seizures / genetics

Substances

  • Glial Fibrillary Acidic Protein
  • DNA Restriction Enzymes

Grant support