De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures.
Actins
/ metabolism
Adolescent
Autistic Disorder
/ genetics
Child
Child, Preschool
Female
GTP Phosphohydrolases
/ metabolism
Humans
Intellectual Disability
/ genetics
Male
Megalencephaly
/ genetics
Models, Molecular
Mutation, Missense
/ genetics
Phosphorylation
Seizures
/ genetics
Signal Transduction
/ genetics
Exome Sequencing
Young Adult
cdc42 GTP-Binding Protein
/ metabolism
p21-Activated Kinases
/ chemistry
rac1 GTP-Binding Protein
/ metabolism
de novo
exome sequencing
intellectual disability
macrocephaly
seizures
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
01 11 2019
01 11 2019
Historique:
received:
02
10
2018
revised:
07
06
2019
accepted:
04
07
2019
pubmed:
11
9
2019
medline:
27
5
2020
entrez:
11
9
2019
Statut:
ppublish
Résumé
Using trio exome sequencing, we identified de novo heterozygous missense variants in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes the p21-activated kinase, a major driver of neuronal development in humans and other organisms. In normal neurons, PAK1 dimers reside in a trans-inhibited conformation, where each autoinhibitory domain covers the kinase domain of the other monomer. Upon GTPase binding via CDC42 or RAC1, the PAK1 dimers dissociate and become activated. All identified variants are located within or close to the autoinhibitory switch domain that is necessary for trans-inhibition of resting PAK1 dimers. Protein modelling supports a model of reduced ability of regular autoinhibition, suggesting a gain of function mechanism for the identified missense variants. Alleviated dissociation into monomers, autophosphorylation and activation of PAK1 influences the actin dynamics of neurite outgrowth. Based on our clinical and genetic data, as well as the role of PAK1 in brain development, we suggest that gain of function pathogenic de novo missense variants in PAK1 lead to moderate-to-severe intellectual disability, macrocephaly caused by the presence of megalencephaly and ventriculomegaly, (febrile) seizures and autism-like behaviour.
Identifiants
pubmed: 31504246
pii: 5556429
doi: 10.1093/brain/awz264
pmc: PMC6821231
doi:
Substances chimiques
Actins
0
RAC1 protein, human
0
PAK1 protein, human
EC 2.7.11.1
p21-Activated Kinases
EC 2.7.11.1
GTP Phosphohydrolases
EC 3.6.1.-
CDC42 protein, human
EC 3.6.5.2
cdc42 GTP-Binding Protein
EC 3.6.5.2
rac1 GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3351-3359Subventions
Organisme : NINDS NIH HHS
ID : K08 NS092898
Pays : United States
Informations de copyright
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.
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