Neuronal impact of patient-specific aberrant NRXN1α splicing.,Nature Genetics

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Neuronal impact of patient-specific aberrant NRXN1α splicing.
Nature Genetics ( IF 31.7 ) Pub Date : 2019-11-29 , DOI: 10.1038/s41588-019-0539-z
Erin Flaherty _{1,

2,

3} , Shijia Zhu _{4,

5,

6} , Natalie Barretto ₃ , Esther Cheng ₃ , P J Michael Deans _{2,

4} , Michael B Fernando _{1,

2,

3} , Nadine Schrode _{2,

4} , Nancy Francoeur _{4,

5} , Alesia Antoine _{4,

5} , Khaled Alganem ₇ , Madeline Halpern ₃ , Gintaras Deikus _{4,

5} , Hardik Shah _{4,

5} , Megan Fitzgerald _{2,

8} , Ian Ladran _{2,

8} , Peter Gochman ₉ , Judith Rapoport ₉ , Nadejda M Tsankova _{1,

2,

10} , Robert McCullumsmith ₇ , Gabriel E Hoffman _{4,

5,

11} , Robert Sebra _{4,

5} , Gang Fang _{4,

5} , Kristen J Brennand _{1,

2,

4,

5,

8,

11}

Affiliation

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Neurosciences, Institute in the College of Medicine & Life Sciences, The University of Toledo, Toledo, OH, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

NRXN1 undergoes extensive alternative splicing, and non-recurrent heterozygous deletions in NRXN1 are strongly associated with neuropsychiatric disorders. We establish that human induced pluripotent stem cell (hiPSC)-derived neurons well represent the diversity of NRXN1α alternative splicing observed in the human brain, cataloguing 123 high-confidence in-frame human NRXN1α isoforms. Patient-derived NRXN1+/- hiPSC-neurons show a greater than twofold reduction in half of the wild-type NRXN1α isoforms and express dozens of novel isoforms from the mutant allele. Reduced neuronal activity in patient-derived NRXN1+/- hiPSC-neurons is ameliorated by overexpression of individual control isoforms in a genotype-dependent manner, whereas individual mutant isoforms decrease neuronal activity levels in control hiPSC-neurons. In a genotype-dependent manner, the phenotypic impact of patient-specific NRXN1+/- mutations can occur through a reduction in wild-type NRXN1α isoform levels as well as the presence of mutant NRXN1α isoforms.

中文翻译：

患者特异性异常 NRXN1α 剪接的神经元影响。

NRXN1 经历广泛的可变剪接，并且 NRXN1 中的非复发性杂合缺失与神经精神疾病密切相关。我们确定人诱导多能干细胞 (hiPSC) 衍生的神经元很好地代表了在人脑中观察到的 NRXN1α 可变剪接的多样性，对 123 个高置信度的框内人 NRXN1α 同种型进行了分类。患者衍生的 NRXN1+/- hiPSC 神经元显示一半的野生型 NRXN1α 同种型减少了两倍以上，并从突变等位基因表达了数十种新的同种型。患者衍生的 NRXN1+/- hiPSC 神经元中降低的神经元活动通过以基因型依赖性方式过表达个体对照亚型得到改善，而个体突变亚型降低对照 hiPSC 神经元中的神经元活动水平。以基因型依赖的方式，

更新日期：2019-11-30

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