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

Xuyu Qian; Ellen M DeGennaro; Maya Talukdar; Shyam K Akula; Abbe Lai; Diane D Shao; Dilenny Gonzalez; Jack H Marciano; Richard S Smith; Norma K Hylton; Edward Yang; J Fernando Bazan; Lee Barrett; Rebecca C Yeh; R Sean Hill; Samantha G Beck; Aoi Otani; Jolly Angad; Tadahiro Mitani; Jennifer E Posey; Davut Pehlivan; Daniel Calame; Hatip Aydin; Osman Yesilbas; Kendall C Parks; Emanuela Argilli; Eleina England; Kiho Im; Ajay Taranath; Hamish S Scott; Christopher P Barnett; Peer Arts; Elliott H Sherr; James R Lupski; Christopher A Walsh

doi:10.1016/j.devcel.2022.09.011

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

Dev Cell. 2022 Oct 24;57(20):2381-2396.e13. doi: 10.1016/j.devcel.2022.09.011. Epub 2022 Oct 12.

Authors

Xuyu Qian¹, Ellen M DeGennaro², Maya Talukdar³, Shyam K Akula⁴, Abbe Lai¹, Diane D Shao⁵, Dilenny Gonzalez⁶, Jack H Marciano⁶, Richard S Smith¹, Norma K Hylton⁷, Edward Yang⁸, J Fernando Bazan⁹, Lee Barrett¹⁰, Rebecca C Yeh⁶, R Sean Hill¹, Samantha G Beck⁶, Aoi Otani¹¹, Jolly Angad¹², Tadahiro Mitani¹², Jennifer E Posey¹², Davut Pehlivan¹³, Daniel Calame¹⁴, Hatip Aydin¹⁵, Osman Yesilbas¹⁶, Kendall C Parks¹⁷, Emanuela Argilli¹⁷, Eleina England¹⁸, Kiho Im¹⁹, Ajay Taranath²⁰, Hamish S Scott²¹, Christopher P Barnett²², Peer Arts²³, Elliott H Sherr²⁴, James R Lupski²⁵, Christopher A Walsh²⁶

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.
⁹ ℏ Bioconsulting LLC, Stillwater, MN 55082, USA.
¹⁰ Department of Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹³ 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.
¹⁴ 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.
¹⁵ Centre of Genetics Diagnosis, Zeynep Kamil Maternity and Children's Training and Research Hospital, Istanbul, Turkey.
¹⁶ Department of Pediatrics, Division of Pediatric Critical Care Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon 61080, Turkey.
¹⁷ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁸ Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁹ Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
²⁰ Department of Medical Imaging, South Australia Medical Imaging, Women's and Children's Hospital, North Adelaide, SA, Australia.
²¹ 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.
²² Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia; Pediatric and Reproductive Genetics Unit, Women's and Children's Hospital, North Adelaide, SA, Australia.
²³ Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, SA, Australia.
²⁴ 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.
²⁵ 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.
²⁶ 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: [email protected].

Abstract

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.

Keywords: apoptosis; cerebral cortex; congenital brain malformation; corpus callosum; development; genetics; kinesin; migration; organoid.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Brain / metabolism
Focal Adhesion Protein-Tyrosine Kinases / metabolism
Humans
Kinesins* / genetics
Mice
Neurons* / metabolism

Substances

Kinesins
Focal Adhesion Protein-Tyrosine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding