Human neurons from Christianson syndrome iPSCs reveal mutation-specific responses to rescue strategies
| Autor: | Laura I. van Dyck, Dipal Nagda, Avner Schlessinger, Sofia B. Lizarraga, Abbie M. Maguire, Michael Schmidt, Diane Hoffman-Kim, Qing Wu, Paul Brito-Vargas, Mara H. Cowen, Liane L. Livi, Li Ma, Matthew F. Pescosolido, Qing Ouyang, Ece D. Gamsiz Uzun, Shanique Alabi, Brian C. Kavanaugh, Eric M. Morrow, Richard N. Jones |
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| Rok vydání: | 2021 |
| Předmět: |
Neurons
Mutation Epilepsy Genetic enhancement Induced Pluripotent Stem Cells Nonsense mutation Genetic Diseases X-Linked General Medicine Postnatal microcephaly Biology medicine.disease_cause Phenotype Article Cell biology Ocular Motility Disorders Intellectual Disability Microcephaly medicine Humans Missense mutation Ataxia Induced pluripotent stem cell Gene |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aaw0682 |
| Popis: | Christianson syndrome (CS), an X-linked neurological disorder characterized by postnatal attenuation of brain growth (postnatal microcephaly), is caused by mutations in SLC9A6 (also termed NHE6), the gene encoding endosomal Na(+)/H(+) exchanger 6 (NHE6). To hasten treatment development, we established CS patient-derived induced pluripotent stem cell (iPSC) lines 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. |
| Databáze: | OpenAIRE |
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