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

By 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 Uzun, Avner Schlessinger, Richard N Jones, Eric M Morrow

Posted 16 Oct 2018
bioRxiv DOI: 10.1101/444232

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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