Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis.

Humans Animals Mice Kinesins / genetics Neurons / metabolism Focal Adhesion Protein-Tyrosine Kinases / metabolism Apoptosis Brain / metabolism
apoptosis cerebral cortex congenital brain malformation corpus callosum development genetics kinesin migration organoid

Journal

Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028

Informations de publication

Date de publication:
24 10 2022
Historique:
received: 06 12 2021
revised: 13 06 2022
accepted: 20 09 2022
pubmed: 14 10 2022
medline: 28 10 2022
entrez: 13 10 2022
Statut: ppublish

Résumé

Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.

Identifiants

DOI: 10.1016/j.devcel.2022.09.011 PMID: 36228617 PMC: PMC10585591
pubmed: 36228617
pii: S1534-5807(22)00681-5
doi: 10.1016/j.devcel.2022.09.011
pmc: PMC10585591
mid: NIHMS1935233
pii:
doi:

Substances chimiques

Kinesins EC 3.6.4.4
Focal Adhesion Protein-Tyrosine Kinases EC 2.7.10.2

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

2381-2396.e13

Subventions

Organisme : NINDS NIH HHS
ID : R01 NS032457
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM144273
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS035129
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM106373
Pays : United States
Organisme : NINDS NIH HHS
ID : R25 NS070682
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007753
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG011758
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories, and J.R.L. is a member of the Scientific Advisory Board of BG. C.A.W. has stock ownership in Maze Therapeutics and is a paid consultant for Third Rock Ventures and Flagship Pioneering.

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Auteurs

Xuyu Qian (X)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Ellen M DeGennaro (EM)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

Maya Talukdar (M)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

Shyam K Akula (SK)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard, MIT MD/PhD Program, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.

Abbe Lai (A)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Diane D Shao (DD)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.

Dilenny Gonzalez (D)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Jack H Marciano (JH)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Richard S Smith (RS)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Norma K Hylton (NK)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard, MIT MD/PhD Program, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.

Edward Yang (E)

Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.

J Fernando Bazan (JF)

ℏ Bioconsulting LLC, Stillwater, MN 55082, USA.

Lee Barrett (L)

Department of Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Rebecca C Yeh (RC)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

R Sean Hill (RS)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Samantha G Beck (SG)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Aoi Otani (A)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Jolly Angad (J)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Tadahiro Mitani (T)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Jennifer E Posey (JE)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Davut Pehlivan (D)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Daniel Calame (D)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Hatip Aydin (H)

Centre of Genetics Diagnosis, Zeynep Kamil Maternity and Children's Training and Research Hospital, Istanbul, Turkey.

Osman Yesilbas (O)

Department of Pediatrics, Division of Pediatric Critical Care Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon 61080, Turkey.

Kendall C Parks (KC)

Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.

Emanuela Argilli (E)

Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.

Eleina England (E)

Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Kiho Im (K)

Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Ajay Taranath (A)

Department of Medical Imaging, South Australia Medical Imaging, Women's and Children's Hospital, North Adelaide, SA, Australia.

Hamish S Scott (HS)

Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, SA, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia; ACRF Cancer Genomics Facility, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, SA, Australia; Australian Genomics, Parkville, VIC, Australia.

Christopher P Barnett (CP)

Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia; Pediatric and Reproductive Genetics Unit, Women's and Children's Hospital, North Adelaide, SA, Australia.

Peer Arts (P)

Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, SA, Australia.

Elliott H Sherr (EH)

Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.

James R Lupski (JR)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.

Christopher A Walsh (CA)

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: christopher.walsh@childrens.harvard.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Loss of non-motor kinesin KIF26A causes...
questionsmedicales.fr › Eucaryotes › Animaux › Loss of non-motor kinesin KIF26A causes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Loss of non-motor kinesin KIF26A causes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Protéines associées aux microtubules › Kinésine › Loss of non-motor kinesin KIF26A causes...
questionsmedicales.fr › Cellules › Neurones › Loss of non-motor kinesin KIF26A causes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › Focal adhesion protein-tyrosine kinases › Loss of non-motor kinesin KIF26A causes...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Loss of non-motor kinesin KIF26A causes...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Loss of non-motor kinesin KIF26A causes...