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

Affiliation

Lizarraga SB(1)(2), Ma L(3)(4), Maguire AM(3)(5), van Dyck LI(3), Wu Q(3)(4)(6), Ouyang Q(3)(4), Kavanaugh BC(4)(5)(7), Nagda D(3), Livi LL(8), Pescosolido MF(3)(4)(5)(7), Schmidt M(3)(4)(5)(7), Alabi S(9), Cowen MH(1)(2), Brito-Vargas P(1)(2), Hoffman-Kim D(8)(10)(11), Gamsiz Uzun ED(6)(12), Schlessinger A(9), Jones RN(13), Morrow EM(14)(4)(5)(7).
Author information:
(1)Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA.
(2)Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC 29208, USA.
(3)Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
(4)Center for Translational Neuroscience, Robert J. and Nancy D. Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University, Providence, RI 02912, USA.
(5)Hassenfeld Child Health Innovation Institute, Brown University, Providence, RI 02912, USA.
(6)Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA.
(7)Developmental Disorders Genetics Research Program, Department of Psychiatry and Human Behavior, Emma Pendleton Bradley Hospital, East Providence, RI 02915, USA.
(8)Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
(9)Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
(10)Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI 02912, USA.
(11)Center for Biomedical Engineering, Brown University, Providence, RI 02912, USA.
(12)Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02912, USA.
(13)Quantitative Sciences Program, Department of Psychiatry and Human Behavior and Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI 02912, USA.
(14)Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA. [Email]

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.