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. 2022 May;63(5):1253-1265.
doi: 10.1111/epi.17198. Epub 2022 Feb 25.

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

Jun-Ru Lin  1 , Ju-Fang Cheng  2 , Yo-Tsen Liu  1   3   4   5 , Ting-Rong Hsu  3   6   7 , Kao-Min Lin  8   9 , Chien Chen  3   4 , Chia-Ling Lin  10 , Meng-Han Tsai  11   12 , Jin-Wu Tsai  1   5   13
Affiliations

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

Jun-Ru Lin et al. Epilepsia. 2022 May.

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.

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

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References

REFERENCES

    1. Portes VD, Pinard JM, Billuart P, Vinet MC, Koulakoff A, Carrié A, et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell. 1998;92(1):51-61.
    1. Francis F, Koulakoff A, Boucher D, Chafey P, Schaar B, Vinet M-C, et al. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron. 1999;23:247-56.
    1. Pilz DT, Kuc J, Matsumoto N, Bodurtha J, Bernadi B, Tassinari CA, et al. Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1. Hum Mol Genet. 1999;8(9):1757-60.
    1. Haverfield EV, Whited AJ, Petras KS, Dobyns WB, Das S. Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia. Eur J Hum Genet. 2009;17(7):911-8.
    1. Pavone L, Rizzo R, Dobyns WB. Clinical manifestations and evaluation of isolated lissencephaly. Childs Nerv Syst. 1993;9:387-90.

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