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Hum Mol Genet. 2018 Jan 15;27(2):224-238. doi: 10.1093/hmg/ddx384.

Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development.

Broix L1,2,3,4,5, Asselin L1,2,3,4, Silva CG6, Ivanova EL1,2,3,4, Tilly P1,2,3,4, Gilet JG1,2,3,4, Lebrun N5, Jagline H1,2,3,4, Muraca G5, Saillour Y5, Drouot N1,2,3,4, Reilly ML7,8,9, Francis F10,11,12, Benmerah A8,9, Bahi-Buisson N7,8, Belvindrah R10,11,12, Nguyen L6, Godin JD1,2,3,4, Chelly J1,2,3,4,13, Hinckelmann MV1,2,3,4.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France.
2
CNRS U7104, Illkirch 67400, France.
3
INSERM U964, Illkirch 67400, France.
4
Université de Strasbourg, Illkirch 67400, France.
5
Institut Cochin, INSERM U1016, CNRS U8104, Paris Descartes University, Paris 75000, France.
6
GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium.
7
Paris Diderot University, Paris 75013, France.
8
INSERM UMR 1163, Paris 75015, France.
9
Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris 75015, France.
10
Inserm UMR-S 839, Paris 75005, France.
11
Sorbonne Université, Université Pierre et Marie Curie, Paris 75000, France.
12
Institut du Fer à Moulin, Paris 75000, France.
13
Service de Diagnostic Génétique, Hôpital Civil de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France.

Abstract

Genetic findings reported by our group and others showed that de novo missense variants in the KIF2A gene underlie malformations of brain development called pachygyria and microcephaly. Though KIF2A is known as member of the Kinesin-13 family involved in the regulation of microtubule end dynamics through its ATP dependent MT-depolymerase activity, how KIF2A variants lead to brain malformations is still largely unknown. Using cellular and in utero electroporation approaches, we show here that KIF2A disease-causing variants disrupts projection neuron positioning and interneuron migration, as well as progenitors proliferation. Interestingly, further dissection of this latter process revealed that ciliogenesis regulation is also altered during progenitors cell cycle. Altogether, our data suggest that deregulation of the coupling between ciliogenesis and cell cycle might contribute to the pathogenesis of KIF2A-related brain malformations. They also raise the issue whether ciliogenesis defects are a hallmark of other brain malformations, such as those related to tubulins and MT-motor proteins variants.

PMID:
29077851
DOI:
10.1093/hmg/ddx384
[Indexed for MEDLINE]

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