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ResearchIn-Press PreviewStem cells Free access | 10.1172/JCI146287
1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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Stratigopoulos, G.
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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LeDuc, C.
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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Williams, D.
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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Tsang, S.
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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Egli, D.
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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Zheng, D.
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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1Department of Medicine, Columbia University, New York, United States of America
2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America
3Department of Pediatrics, Columbia University, New York, United States of America
4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America
5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America
6Early Research and Development, Levo Therapeutics, Skokie, United States of America
7Institute for Genomic Medicine, Columbia University, New York, United States of America
8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America
9Department of Pathology and Cell Biology, Columbia University, New York, United States of America
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Published February 25, 2021 - More info
Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell (iPSCs)-derived hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuron differentiation efficiency but caused morphological defects including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons identified several downregulated pathways including insulin and cAMP signaling, and axon guidance. Additional studies demonstrated that BBS1M390R and BBS10C91fsX95 mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS10C91fsX95 neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in BBS1M390R and BBS10C91fsX95 iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.