Human neurons from Christianson syndrome iPSCs reveal mutation-specific responses to rescue strategies.
Human neurons from Christianson syndrome iPSCs reveal mutation-specific responses to rescue strategies.
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DOI：
10.1126/scitranslmed.aaw0682
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发表时间：
2021-02-10
影响因子：
17.1
通讯作者：
Morrow EM
中科院分区：
文献类型：
--
作者：
Lizarraga SB;Ma L;Maguire AM;van Dyck LI;Wu Q;Ouyang Q;Kavanaugh BC;Nagda D;Livi LL;Pescosolido MF;Schmidt M;Alabi S;Cowen MH;Brito-Vargas P;Hoffman-Kim D;Gamsiz Uzun ED;Schlessinger A;Jones RN;Morrow EM
Christianson综合征（CS）是一种X连锁神经系统疾病，其特征是出生后脑生长减弱（出生后小头畸形），由SLC 9A 6（也称为NHE 6）突变引起，SLC 9A 6是编码内体Na+/H+交换器6（NHE 6）的基因。为了加速治疗开发，我们建立了CS患者来源的诱导多能干细胞（iPSC）系，代表突变谱，以及生物学相关和同基因对照系。我们证明了致病性突变通过多种机制导致蛋白质功能丧失：大多数突变由于无义介导的mRNA衰变而导致mRNA丧失;然而，复发性错义突变（G383 D突变）具有功能丧失和显性负活性。无论突变如何，所有患者来源的神经元都表现出神经突生长和树枝化减少，这可能是患者出生后大脑生长减少的基础。表型拯救策略显示突变特异性反应：基因转移策略在无义突变中有效，但在G383 D突变中无效，其中残留蛋白质似乎干扰拯救。相反，外源性营养因子（BDNF或IGF-1）的应用拯救了所有突变的树枝状表型。这些结果可以指导治疗CS的发展，包括基因治疗策略，其中我们的数据表明，治疗反应可能取决于突变的类别。来自患者来源的iPSC的神经元对Christianson综合征的潜在治疗策略表现出突变特异性反应。
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. Neurons from patient-derived iPSCs demonstrate mutation-specific responses to potential therapeutic strategies for Christianson syndrome.
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影响因子：
3
作者：
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通讯作者：
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影响因子：
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影响因子：
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DOI：
10.1073/pnas.1311141111
发表时间：
2014-03-25
影响因子：
11.1
作者：
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