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Accepted Manuscript

A novel TAF1 variant affects gene expression and is associated with x-linked TAF1 intellectual disability syndrome

Sarah E Hurst, Erika Liktor-Busa, Aubin Moutal, Sara Parker, Sydney Rice, Szabolcs Szelinger, Grant Senner, Michael Hammer, Laurel Johnstone, Keri Ramsey, Vinodh Narayanan, Samantha Perez-Miller, May Khanna, Heather Dahlin, Karen Lewis, David Craig, Edith H Wang, Rajesh Khanna, Mark A. Nelson
Neuronal Signaling Jun 25, 2018, NS20180141; DOI: 10.1042/NS20180141
Sarah E Hurst
Pathology, University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona, 85724, United States
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Erika Liktor-Busa
Pathology, University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona, United States
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Aubin Moutal
Pharmacology, University of Arizona, Tucson, Arizona, United States
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Sara Parker
University of Arizona, Tucson, Arizona, United States
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Sydney Rice
University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona, 85724, United States
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Szabolcs Szelinger
The Translational Genomics Research Institute, Phoenix, Arizona, United States
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Grant Senner
University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona, 85724, United States
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Michael Hammer
University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona, 85724, United States
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Laurel Johnstone
University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona, 85724, United States
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Keri Ramsey
The Translational Genomics Research Institute, Phoenix, Arizona, United States
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Vinodh Narayanan
The Translational Genomics Research Institute, Phoenix, Arizona, United States
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Samantha Perez-Miller
University of Arizona, Tucson, Arizona, United States
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May Khanna
University of Arizona, Tucson, Arizona, United States
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Heather Dahlin
University of Washington, Seattle, Washington, United States
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Karen Lewis
University of Washington, Seattle, Washington, United States
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David Craig
The Translational Genomics Research Institute, Phoenix, Arizona, United States
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Edith H Wang
University of Washington, Seattle, Washington, United States
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Rajesh Khanna
Departments of Pharmacology, Anesthesiology, and Neuroscience, University of Arizona, 1501 North Campbell Avenue, Tucson, Arizona, Arizona, AZ 85724, United States
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Mark A. Nelson
Pathology, University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona, 85724, United States
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  • For correspondence: mnelson@pathology.arizona.edu
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Abstract

We investigated the genome of a 5-year old male who presented with global developmental delay (motor, cognitive, and speech), hypotonia, possibly ataxia, and cerebellar hypoplasia of unknown origin. Whole genome sequencing and mRNA-sequencing were performed on a family containing an affected proband, his unaffected parents and maternal grandfather. To explore the molecular and functional consequences of the variant, we performed cell proliferation assays, qRT-PCR array, immunoblotting, calcium imaging, and neurite outgrowth experiments in SH-SY5Y neuroblastoma cells to compare the properties of the wild type TAF1, deletion of TAF1, and TAF1 variant p.Ser1600Gly samples. The whole genome data identified several gene variants. However, the genome sequence data failed to implicate a candidate gene as many of the variants were of unknown significance. By combining genome sequence data with transcriptomic data, a probable candidate variant, p.Ser1600Gly, emerged in TAF1 . Moreover, the RNA-seq data revealed a 90:10 extremely skewed X-chromosome inactivation in the mother. Our results show that neuronal ion channel genes were differentially expressed between TAF1 deletion and TAF1 variant p.Ser1600Gly cells, when compared to their respective controls, and that the TAF1 variant may impair neuronal differentiation and cell proliferation.  Taken together, our data suggests that this novel variant in TAF1 plays a key role in the development of a recently described X-linked syndrome, TAF1 intellectual disability syndrome, and further extends our knowledge of a potential link between TAF1 deficiency and defects in neuronal cell function.

  • TAF-1
  • whole genome sequencing
  • RNA sequencing
  • X-chromosome inactivation
  • CACNA1G
  • cyclin D1
  • Received April 11, 2018.
  • Revision received June 18, 2018.
  • Accepted June 25, 2018.
  • ©2018 The Author(s)

This is an Accepted Manuscript; not the final Version of Record. You are encouraged to use the final Version of Record that, when published, will replace this manuscript and be freely available under a Creative Commons licence.

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A novel TAF1 variant affects gene expression and is associated with x-linked TAF1 intellectual disability syndrome
Sarah E Hurst, Erika Liktor-Busa, Aubin Moutal, Sara Parker, Sydney Rice, Szabolcs Szelinger, Grant Senner, Michael Hammer, Laurel Johnstone, Keri Ramsey, Vinodh Narayanan, Samantha Perez-Miller, May Khanna, Heather Dahlin, Karen Lewis, David Craig, Edith H Wang, Rajesh Khanna, Mark A. Nelson
Neuronal Signaling Jun 2018, NS20180141; DOI: 10.1042/NS20180141
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A novel TAF1 variant affects gene expression and is associated with x-linked TAF1 intellectual disability syndrome
Sarah E Hurst, Erika Liktor-Busa, Aubin Moutal, Sara Parker, Sydney Rice, Szabolcs Szelinger, Grant Senner, Michael Hammer, Laurel Johnstone, Keri Ramsey, Vinodh Narayanan, Samantha Perez-Miller, May Khanna, Heather Dahlin, Karen Lewis, David Craig, Edith H Wang, Rajesh Khanna, Mark A. Nelson
Neuronal Signaling Jun 2018, NS20180141; DOI: 10.1042/NS20180141

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Keywords

TAF-1
whole genome sequencing
RNA sequencing
X-chromosome inactivation
CACNA1G
cyclin D1

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