4.5 Article

Novel lissencephaly-associated DCX variants in the C-terminal DCX domain affect microtubule binding and dynamics

Journal

EPILEPSIA
Volume 63, Issue 5, Pages 1253-1265

Publisher

WILEY
DOI: 10.1111/epi.17198

Keywords

DCX; doublecortin; epilepsy; lissencephaly; microtubule binding protein; neuronal migration; subcortical band heterotopia

Funding

  1. Ministry of Science and Technology (MOST) [105-2633-B-009-003, 106-2321-B-075-001, 106-2628-B-010-002-MY3, 107-2321-B-075-001, 107-2221-E-010-014, 108-2638-B-010-001-MY2, 108-2321-B-010-011-MY2, 110-2628-B-A49A-506]
  2. Taipei Veterans General Hospital-University System of Taiwan [VGHUST109-V1-5-3, VGHUST110-G1-5-3]
  3. National Health Research Institutes (NHRI) [NHRI-EX109-10904NI]
  4. Yin Yen-Liang Foundation Development and Construction Plan [107F-M01-0502]
  5. Brain Research Center, National Yang Ming Chiao Tung University through the Featured Areas Research Center Program
  6. MOST [MOST 105-2314-B-075-066, 107-2314-B-075-020, 109-2314-B-075-055, 110-2628-B-075-014-, MOST110-2314-B-182A-076-MY3]
  7. NHRI [NHRI-EX105-10507EC, NHRI-EX106-10507EC, NHRI-EX110-11022NI]
  8. Yen Tjing Ling Medical Foundation [CI-106-6]
  9. Taipei Veterans General Hospital [V107C-152, V108C-075, V110C-080, VGHUST106-G7-5-1, VGHUST107-G7-1-3, VGHUST108-G7-1-3]
  10. MOE [109BRC-B408]
  11. Chang Gung Medical Foundation [CMRPG8K0632]
  12. National Core Facility Program for Biotechnology, MOST, Taiwan

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This study aims to investigate how DCX variants affect neuronal migration defects during brain development. Through experiments, it was found that these variants decreased the microtubule binding ability and dynamics of DCX, potentially leading to neuronal migration defects.
Objective Pathogenic variants in DCX on the X chromosome lead to lissencephaly and subcortical band heterotopia (SBH), brain malformations caused by neuronal migration defects. Its product doublecortin (DCX) binds to microtubules to modulate microtubule polymerization. How pathogenic DCX variants affect these activities remains not fully investigated. Methods DCX variants were identified using whole exome and Sanger sequencing from six families with lissencephaly/SBH. We examined how these variants affect DCX functions using microtubule binding, regrowth, and colocalization assays. Results We found novel DCX variants p.Val177AlafsTer31 and p.Gly188Trp, as well as reported variants p.Arg196His, p.Lys202Met, and p.Thr203Ala. Incidentally, all of the missense variants were clustered on the C-terminal DCX domain. The microtubule binding ability was significantly decreased in p.Val177AlafsTer31, p.Gly188Trp, p.Lys202Met, and previously reported p.Asp262Gly variants. Furthermore, expression of p.Val177AlafsTer31, p.Gly188Trp, p.Arg196His, p.Lys202Met, and p.Asp262Gly variants hindered microtubule growth in cells. There were also decreases in the colocalization of p.Val177AlafsTer31, p.Thr203Ala, and p.Asp262Gly variants to microtubules. Significance Our results indicate that these variants in the C-terminal DCX domain altered microtubule binding and dynamics, which may underlie neuronal migration defects during brain development.

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