Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder.
MARK2
agyria
autosomal recessive
lissencephaly
neurodevelopmental disorder
pachygyria
patronin
tubulinopathy
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 11 2022
03 11 2022
Historique:
received:
04
08
2022
accepted:
27
09
2022
pubmed:
26
10
2022
medline:
9
11
2022
entrez:
25
10
2022
Statut:
ppublish
Résumé
Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.
Identifiants
pubmed: 36283405
pii: S0002-9297(22)00415-3
doi: 10.1016/j.ajhg.2022.09.012
pmc: PMC9674946
pii:
doi:
Substances chimiques
Tubulin
0
CAMSAP1 protein, human
0
Microtubule-Associated Proteins
0
Camsap1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2068-2079Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIDCR NIH HHS
ID : R01 DE027091
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_18047
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1001931
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1002279
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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