Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.
Adolescent
Adult
Age of Onset
Animals
Centrosome
/ pathology
Child
Child, Preschool
Chromosome Aberrations
Classical Lissencephalies and Subcortical Band Heterotopias
/ diagnostic imaging
Cytoskeletal Proteins
/ genetics
Female
Gene Knockdown Techniques
Genetic Variation
Heterozygote
Humans
Infant
Magnetic Resonance Imaging
Male
Mice
Mutation
/ genetics
Oncogene Proteins, Fusion
/ genetics
Pedigree
Seizures
/ etiology
Young Adult
CEP85L
centrosome
lissencephaly
pachygyria
posterior predominant
subcortical band heterotopia
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
22 04 2020
22 04 2020
Historique:
received:
04
09
2019
revised:
26
11
2019
accepted:
22
01
2020
pubmed:
26
2
2020
medline:
12
8
2020
entrez:
26
2
2020
Statut:
ppublish
Résumé
Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.
Identifiants
pubmed: 32097630
pii: S0896-6273(20)30053-2
doi: 10.1016/j.neuron.2020.01.027
pmc: PMC7357395
mid: NIHMS1569025
pii:
doi:
Substances chimiques
CEP85L protein, human
0
Cytoskeletal Proteins
0
Oncogene Proteins, Fusion
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
237-245.e8Subventions
Organisme : NICHD NIH HHS
ID : P50 HD103524
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS069605
Pays : United States
Organisme : NHGRI NIH HHS
ID : R25 HG007153
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006493
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests N.D. has served on scientific advisory boards for Sarepta, Biomarin, and Avexis. I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, and Xenon Pharmaceuticals; editorial boards of the Annals of Neurology, Neurology, and Epileptic Disorders; may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has received speaker honoraria from GlaxoSmithKline, Athena Diagnostics, UCB, BioMarin, and Eisai; and has received funding for travel from Athena Diagnostics, UCB, Biocodex, GlaxoSmithKline, Biomarin, and Eisai. H.C.M. is a member of scientific advisory boards for Lennox Gastaut Syndrome Foundation, Dravet Syndrome Foundation, and SPARK. K.R. has served on advisory boards for UCB, Eisai, Liva Nova, and Novartis; has received research funding from UCB, Jansen-Cilag, Novartis, Zogenix, Liva Nova, Eisai, and AFT Pharmaceuticals; and received speaker honoraria from UCB and Biomarin. All other authors declare no competing interests.
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