Novel lissencephaly-associated DCX variants in the C-terminal DCX domain affect microtubule binding and dynamics.
Epilepsia
; 63(5): 1253-1265, 2022 05.
Article
en En
| MEDLINE
| ID: mdl-35213059
ABSTRACT
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neuropéptidos
/
Lisencefalia
/
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Epilepsia
Año:
2022
Tipo del documento:
Article
País de afiliación:
Taiwán