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Related Experiment Videos

Doublecortin mutations cluster in evolutionarily conserved functional domains.

T Sapir1, D Horesh, M Caspi

  • 1Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.

Human Molecular Genetics
|April 6, 2000
PubMed
Summary
This summary is machine-generated.

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Mutations in the doublecortin (DCX) gene disrupt brain development by affecting microtubule interactions. Specific mutations within the conserved Doublecortin (DC) domain impair tubulin binding and microtubule polymerization, leading to developmental disorders.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Mutations in the X-linked doublecortin (DCX) gene cause lissencephaly in males and subcortical laminar heterotopia in females.
  • DCX protein is known to interact with and stabilize microtubules, crucial for neuronal development.
  • Previous studies identified various mutations, including missense, nonsense, and splice site mutations, throughout the DCX gene.

Purpose of the Study:

  • To analyze the evolutionarily conserved Doublecortin (DC) domain within DCX and related proteins.
  • To investigate the role of the tandem repeats within the DC domain in microtubule binding and polymerization.
  • To determine the functional consequences of specific DCX mutations on the microtubule cytoskeleton.

Main Methods:

  • Sequence analysis of DCX and DCX-like proteins across different organisms to identify conserved domains.

Related Experiment Videos

  • In vitro and in vivo expression of DCX and DCLK repeats to assess tubulin and microtubule interactions.
  • Overexpression of seven patient-derived DCX mutations in COS7 cells to observe effects on the microtubule cytoskeleton.

    • Main Results:

    • A conserved Doublecortin (DC) domain, consisting of two tandem 80 amino acid repeats, was identified, primarily in the N-terminus.
    • The first repeat of the DC domain binds tubulin and enhances microtubule polymerization.
    • Several DCX mutations disrupt the microtubule cytoskeleton, with the Y125H mutation showing the most severe effect both in cells and in vitro.

    Conclusions:

    • The tandem repeats within the Doublecortin (DC) domain are critical for microtubule binding and polymerization.
    • Missense mutations within these conserved repeats disrupt DCX function, impacting brain development.
    • Understanding DCX-microtubule interactions is essential for comprehending normal and abnormal brain development.