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Related Experiment Videos

GFAP mutations in Alexander disease.

Rong Li1, Albee Messing, James E Goldman

  • 1Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0021, USA.

International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience
|August 15, 2002
PubMed
Summary

Alexander disease, a fatal neurological disorder, is caused by dominant mutations in the glial fibrillary acidic protein (GFAP) gene. These GFAP mutations likely result in a toxic gain of function, leading to disease pathogenesis.

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Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Alexander disease is a rare, fatal central nervous system disorder.
  • It is characterized by Rosenthal fibers in astrocytes, composed of glial fibrillary acidic protein (GFAP).
  • Distinct infantile, juvenile, and adult forms exist with varied clinical presentations.

Purpose of the Study:

  • To investigate the genetic basis of Alexander disease.
  • To determine the role of GFAP mutations in disease development.
  • To elucidate the mechanism underlying Alexander disease pathogenesis.

Main Methods:

  • Genetic sequencing of the GFAP gene in Alexander disease patients.
  • Analysis of GFAP mutations in different disease forms.
  • Comparison of Alexander disease mutations with those in other intermediate filament diseases.

Related Experiment Videos

  • Assessment of GFAP intermediate filament network in patient astrocytes and GFAP-null mice.

    • Main Results:

    • GFAP coding mutations were identified in most Alexander disease cases, including infantile and juvenile forms.
    • Mutations were located in conserved central rod and variable tail regions of GFAP.
    • All identified mutations were heterozygous missense, often de novo.
    • Alexander disease astrocytes showed normal intermediate filaments, and GFAP-null mice were asymptomatic.

    Conclusions:

    • Alexander disease is primarily caused by dominant, de novo GFAP mutations.
    • The disease likely results from a toxic gain of function, not loss of function.
    • Mutations may impair GFAP filament assembly, leading to toxic intermediate accumulation.