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Human neurons from Christianson syndrome iPSCs reveal allele-specific responses to rescue strategies

View ORCID ProfileSofia B. Lizarraga, Abbie M. Maguire, Li Ma, Laura I. van Dyck, Qing Wu, Dipal Nagda, Liane L. Livi, Matthew F. Pescosolido, Michael Schmidt, Shanique Alabi, Mara H. Cowen, Paul Brito-Vargas, Diane Hoffman-Kim, Ece D. Gamsiz Uzun, Avner Schlessinger, Richard N. Jones, View ORCID ProfileEric M. Morrow
doi: https://doi.org/10.1101/444232
Sofia B. Lizarraga
1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, USA
2Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, South Carolina, USA
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  • ORCID record for Sofia B. Lizarraga
Abbie M. Maguire
3Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
4Hassenfeld Child Health Innovation Institute, Brown University, Providence, Rhode Island, USA
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Li Ma
3Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
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Laura I. van Dyck
3Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
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Qing Wu
3Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
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Dipal Nagda
3Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
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Liane L. Livi
5Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island, USA
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Matthew F. Pescosolido
3Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
4Hassenfeld Child Health Innovation Institute, Brown University, Providence, Rhode Island, USA
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Michael Schmidt
3Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
4Hassenfeld Child Health Innovation Institute, Brown University, Providence, Rhode Island, USA
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Shanique Alabi
6Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Mara H. Cowen
1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, USA
2Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, South Carolina, USA
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Paul Brito-Vargas
1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, USA
2Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, South Carolina, USA
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Diane Hoffman-Kim
5Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island, USA
7Carney Institute for Brain Science, Brown University, Providence, Rhode Island, USA
8Center for Biomedical Engineering, Brown University, Providence, Rhode Island, USA
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Ece D. Gamsiz Uzun
9Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
10Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA
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Avner Schlessinger
6Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Richard N. Jones
11Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
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Eric M. Morrow
3Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
4Hassenfeld Child Health Innovation Institute, Brown University, Providence, Rhode Island, USA
7Carney Institute for Brain Science, Brown University, Providence, Rhode Island, USA
10Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA
11Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
12Developmental Disorders Genetics Research Program, Emma Pendleton Bradley Hospital, East Providence, Rhode Island, USA
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  • ORCID record for Eric M. Morrow
  • For correspondence: eric_morrow@brown.edu
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Abstract

Human genetic disorders provide a powerful lens to understanding the human brain. Induced pluripotent stem cells (iPSC) represent an important, new resource for mechanistic studies and therapeutic development. Christianson syndrome (CS), an X-linked neurological disorder with attenuation of brain growth postnatally (postnatal microcephaly), is caused by mutations in SLC9A6, the gene encoding endosomal Na+/H+ exchanger 6 (NHE6). We developed CS iPSC lines from patients with a mutational spectrum, as well as robust biologically-related and isogenic controls. We demonstrate that mutations in CS lead to loss of protein function by a variety of mechanisms. Regardless of mutation, all patient-derived neurons demonstrate reduced neurite growth and arborization, likely underlying diminished postnatal brain growth in patients. Additionally, phenotype rescue strategies show allele-specific responses: a gene replacement strategy shows efficacy in nonsense mutations but not in a missense mutation, whereas application of exogenous trophic factors (BDNF or IGF-1) rescues arborization phenotypes across all mutations. Our data emphasize the important principle of personalized medicine whereby success of some therapeutic strategies may be more linked to patient genotype than others.

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Posted October 16, 2018.
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Human neurons from Christianson syndrome iPSCs reveal allele-specific responses to rescue strategies
Sofia B. Lizarraga, Abbie M. Maguire, Li Ma, Laura I. van Dyck, Qing Wu, Dipal Nagda, Liane L. Livi, Matthew F. Pescosolido, Michael Schmidt, Shanique Alabi, Mara H. Cowen, Paul Brito-Vargas, Diane Hoffman-Kim, Ece D. Gamsiz Uzun, Avner Schlessinger, Richard N. Jones, Eric M. Morrow
bioRxiv 444232; doi: https://doi.org/10.1101/444232
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Human neurons from Christianson syndrome iPSCs reveal allele-specific responses to rescue strategies
Sofia B. Lizarraga, Abbie M. Maguire, Li Ma, Laura I. van Dyck, Qing Wu, Dipal Nagda, Liane L. Livi, Matthew F. Pescosolido, Michael Schmidt, Shanique Alabi, Mara H. Cowen, Paul Brito-Vargas, Diane Hoffman-Kim, Ece D. Gamsiz Uzun, Avner Schlessinger, Richard N. Jones, Eric M. Morrow
bioRxiv 444232; doi: https://doi.org/10.1101/444232

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