Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development.
Autism is a prevailing neurodevelopmental disorder with a large genetic/genomic component. Recently, the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) gene was implicated as a risk factor for autism spectrum disorder (ASD). We identified five DYRK1A variants in ASD patients and found that the dose of DYRK1A protein has a crucial role in various aspects of postnatal neural development. Dyrk1a loss of function and gain of function led to defects in dendritic growth, dendritic spine development and radial migration during cortical development. Importantly, two autism-associated truncations, R205X and E239X, were shown to be Dyrk1a loss-of-function mutants. Studies of the truncated Dyrk1a mutants may provide new insights into the role of Dyrk1a in brain development, as well as the role of Dyrk1a loss of function in the pathophysiology of autism.
Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China.
T
T
Dang
Exome Sequencing Collaboration at Boston Children's Hospital and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
W Y
WY
Duan
Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
B
B
Yu
Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
D L
DL
Tong
Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
C
C
Cheng
Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Y F
YF
Zhang
Exome Sequencing Collaboration at Boston Children's Hospital and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
W
W
Wu
Exome Sequencing Collaboration at Boston Children's Hospital and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
K
K
Ye
Exome Sequencing Collaboration at Boston Children's Hospital and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
W X
WX
Zhang
Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China.|Exome Sequencing Collaboration at Boston Children's Hospital and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
M
M
Wu
Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China.|Exome Sequencing Collaboration at Boston Children's Hospital and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
B B
BB
Wu
Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China.|Exome Sequencing Collaboration at Boston Children's Hospital and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
Y
Y
An
Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Z L
ZL
Qiu
Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China.|Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
B L
BL
Wu
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism; D001321:Autistic Disorder / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003712:Dendrites / Q000235:genetics / Q000378:metabolism; D049229:Dendritic Spines / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D000097603:Dyrk Kinases
D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases