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

Sofia B. Lizarraga, Li Ma, Abbie M. Maguire, Laura I. van Dyck, Qing Wu, Qing Ouyang, Brian C. Kavanaugh, 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

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Christianson syndrome (CS), an X-linked neurological disorder characterized by postnatal attenuation of brain growth (postnatal microcephaly), is caused by mutations in SLC9A6, the gene encoding endosomal Na+/H+ exchanger 6 (NHE6). To hasten treatment development, we established induced pluripotent stem cell (iPSC) lines from patients with CS representing a mutational spectrum, as well as biologically related and isogenic control lines. We demonstrated that pathogenic mutations lead to loss of protein function by a variety of mechanisms: The majority of mutations caused loss of mRNA due to nonsense-mediated mRNA decay; however, a recurrent, missense mutation (the G383D mutation) had both loss-of-function and dominant-negative activities. Regardless of mutation, all patient-derived neurons demonstrated reduced neurite growth and arborization, likely underlying diminished postnatal brain growth in patients. Phenotype rescue strategies showed mutation-specific responses: A gene transfer strategy was effective in nonsense mutations, but not in the G383D mutation, wherein residual protein appeared to interfere with rescue. In contrast, application of exogenous trophic factors (BDNF or IGF-1) rescued arborization phenotypes across all mutations. These results may guide treatment development in CS, including gene therapy strategies wherein our data suggest that response to treatment may be dictated by the class of mutation.

Original languageEnglish
Article numbereaaw0682
JournalScience Translational Medicine
Issue number580
StatePublished - 10 Feb 2021


Dive into the research topics of 'Human neurons from Christianson syndrome iPSCs reveal mutation-specific responses to rescue strategies'. Together they form a unique fingerprint.

Cite this