TY - JOUR
T1 - N-terminal variant Asp14Asn of the human p70 S6 Kinase 1 enhances translational signaling causing different effects in developing and mature neuronal cells
AU - Venkatasubramani, Janani Priya
AU - Subramanyam, Prakash
AU - Pal, Rakhi
AU - Reddy, Bharath K.
AU - Srinivasan, Durga Jeyalakshmi
AU - Chattarji, Sumantra
AU - Iossifov, Ivan
AU - Klann, Eric
AU - Bhattacharya, Aditi
N1 - Funding Information:
This work was supported by funds from the Department of Biotechnology (DBT), Govt. Of India and Charles. H. Revson Foundation to A.B. We also acknowledge the Central Imaging and Flow Facility, Bangalore Life Science Cluster. Animal work in the inStem Animal Care and Resource Center was partially supported by the National Mouse Research Resource (NaMoR) grant from the DBT. We would like to thank the support extended by Prof. Henry Colecraft, Columbia University Medical Center, Dr. Heather Bowling, NYU and Dr. Sunil Laxman, inStem. Kanika Gupta and Shudhriti Ghosh-Dastidar are thanked for assistance with confocal imaging.
Funding Information:
This work was supported by funds from the Department of Biotechnology (DBT), Govt. Of India and Charles. H. Revson Foundation to A.B. We also acknowledge the Central Imaging and Flow Facility, Bangalore Life Science Cluster. Animal work in the inStem Animal Care and Resource Center was partially supported by the National Mouse Research Resource (NaMoR) grant from the DBT. We would like to thank the support extended by Prof. Henry Colecraft, Columbia University Medical Center, Dr. Heather Bowling, NYU and Dr. Sunil Laxman, inStem. Kanika Gupta and Shudhriti Ghosh-Dastidar are thanked for assistance with confocal imaging.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/5
Y1 - 2020/5
N2 - The ribosomal p70 S6 Kinase 1 (S6K1) has been implicated in the etiology of complex neurological diseases including autism, depression and dementia. Though no major gene disruption has been reported in humans in RPS6KB1, single nucleotide variants (SNVs) causing missense mutations have been identified, which have not been assessed for their impact on protein function. These S6K1 mutations have the potential to influence disease progression and treatment response. We mined the Simon Simplex Collection (SSC) and SPARK autism database to find inherited SNVs in S6K1 and characterized the effect of two missense SNVs, Asp14Asn (allele frequency = 0.03282%) and Glu44Gln (allele frequency = 0.0008244%), on S6K1 function in HEK293, human ES cells and primary neurons. Expressing Asp14Asn in HEK293 cells resulted in increased basal phosphorylation of downstream targets of S6K1 and increased de novo translation. This variant also showed blunted response to the specific S6K1 inhibitor, FS-115. In human embryonic cell line Shef4, Asp14Asn enhanced spontaneous neural fate specification in the absence of differentiating growth factors. In addition to enhanced translation, neurons expressing Asp14Asn exhibited impaired dendritic arborization and increased levels of phosphorylated ERK 1/2. Finally, in the SSC families tracked, Asp14Asn segregated with lower IQ scores when found in the autistic individual rather than the unaffected sibling. The Glu44Gln mutation showed a milder, but opposite phenotype in HEK cells as compared to Asp14Asn. Although the Glu44Gln mutation displayed increased neuronal translation, it had no impact on neuronal morphology. Our results provide the first characterization of naturally occurring human S6K1 variants on cognitive phenotype, neuronal morphology and maturation, underscoring again the importance of translation control in neural development and plasticity.
AB - The ribosomal p70 S6 Kinase 1 (S6K1) has been implicated in the etiology of complex neurological diseases including autism, depression and dementia. Though no major gene disruption has been reported in humans in RPS6KB1, single nucleotide variants (SNVs) causing missense mutations have been identified, which have not been assessed for their impact on protein function. These S6K1 mutations have the potential to influence disease progression and treatment response. We mined the Simon Simplex Collection (SSC) and SPARK autism database to find inherited SNVs in S6K1 and characterized the effect of two missense SNVs, Asp14Asn (allele frequency = 0.03282%) and Glu44Gln (allele frequency = 0.0008244%), on S6K1 function in HEK293, human ES cells and primary neurons. Expressing Asp14Asn in HEK293 cells resulted in increased basal phosphorylation of downstream targets of S6K1 and increased de novo translation. This variant also showed blunted response to the specific S6K1 inhibitor, FS-115. In human embryonic cell line Shef4, Asp14Asn enhanced spontaneous neural fate specification in the absence of differentiating growth factors. In addition to enhanced translation, neurons expressing Asp14Asn exhibited impaired dendritic arborization and increased levels of phosphorylated ERK 1/2. Finally, in the SSC families tracked, Asp14Asn segregated with lower IQ scores when found in the autistic individual rather than the unaffected sibling. The Glu44Gln mutation showed a milder, but opposite phenotype in HEK cells as compared to Asp14Asn. Although the Glu44Gln mutation displayed increased neuronal translation, it had no impact on neuronal morphology. Our results provide the first characterization of naturally occurring human S6K1 variants on cognitive phenotype, neuronal morphology and maturation, underscoring again the importance of translation control in neural development and plasticity.
KW - Autism
KW - Kinase
KW - Neuron
KW - S6K1
KW - Signaling
KW - Single nucleotide variant
KW - Translation
KW - mTOR
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U2 - 10.1016/j.nlm.2020.107203
DO - 10.1016/j.nlm.2020.107203
M3 - Article
C2 - 32147585
AN - SCOPUS:85081244491
SN - 1074-7427
VL - 171
JO - Neurobiology of Learning and Memory
JF - Neurobiology of Learning and Memory
M1 - 107203
ER -