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To each mutation its own treatment
Mutations in the gene encoding the endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome (CS), a neurological disease associated with epilepsy, reduced brain growth, and impaired cognitive abilities. To understand the mechanisms involved in disease pathophysiology and to identify potential treatments, Lizarraga et al. used five induced pluripotent stem cell (iPSC) lines from patients with CS harboring different mutations. Most of the mutations lead to loss of protein, with one exception, that which is associated with a complex loss-of-function mechanism. Gene therapy was shown to rescue cellular abnormalities in a mutation-specific fashion, whereas administration of exogenous trophic factors was effective in all the lines examined.
Abstract
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.
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