A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation

Clemer Abad; Melissa M Cook; Lei Cao; Julie R Jones; Nalini R Rao; Lynn Dukes-Rimsky; Rini Pauly; Cindy Skinner; Yunsheng Wang; Feng Luo; Roger E Stevenson; Katherina Walz; Anand K Srivastava

doi:10.3390/biology7020031

A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation

Biology (Basel). 2018 May 24;7(2):31. doi: 10.3390/biology7020031.

Authors

Clemer Abad¹, Melissa M Cook², Lei Cao³, Julie R Jones⁴, Nalini R Rao⁵, Lynn Dukes-Rimsky⁶, Rini Pauly⁷, Cindy Skinner⁸, Yunsheng Wang⁹, Feng Luo¹⁰, Roger E Stevenson¹¹, Katherina Walz^{12

13}, Anand K Srivastava^{14

15}

Affiliations

¹ John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA. cabad@med.miami.edu.
² J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA. mcook@ggc.org.
³ John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA. LCao@med.miami.edu.
⁴ Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA. juliejones@ggc.org.
⁵ John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA. n.rao@miami.edu.
⁶ J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA. ldrimsky@ggc.org.
⁷ J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA. rpauly@ggc.org.
⁸ J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA. cds11251977@gmail.com.
⁹ School of Computing, Clemson University, Clemson, SC 29634, USA. yunshew@g.clemson.edu.
¹⁰ School of Computing, Clemson University, Clemson, SC 29634, USA. luofeng@clemson.edu.
¹¹ J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA. res@ggc.org.
¹² John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA. KWalz@med.miami.edu.
¹³ Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, FL 33136, USA. KWalz@med.miami.edu.
¹⁴ J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA. anand@ggc.org.
¹⁵ Department of Genetics and Biochemsitry, Clemson University, Clemson, SC 29634, USA. anand@ggc.org.

Abstract

Deletions and mutations involving the Retinoic Acid Induced 1 (RAI1) gene at 17p11.2 cause Smith-Magenis syndrome (SMS). Here we report a patient with autism as the main clinical presentation, with some SMS-like features and a rare de novo RAI1 gene mutation, c.3440G > A (p.R1147Q). We functionally characterized the RAI1 p.R1147Q mutant protein. The mutation, located near the nuclear localization signal, had no effect on the subcellular localization of the mutant protein. However, similar to previously reported RAI1 missense mutations in SMS patients, the RAI1 p.R1147Q mutant protein showed a significant deficiency in activating in vivo transcription of a reporter gene driven by a BDNF (brain-derived neurotrophic factor) intronic enhancer. In addition, expression of other genes associated with neurobehavioral abnormalities and/or neurodevelopmental disorders were found to be altered in this patient. These results suggest a likely contribution of RAI1, either alone or in combination of other factors, to social behavior and reinforce the RAI1 gene as a candidate gene in patients with autistic manifestations or social behavioral abnormalities.

Keywords: RAI1; Smith-Magenis syndrome; autism spectrum disorder; mutation; neurodevelopmental disorder.

Grants and funding

R01 HD039331/HD/NICHD NIH HHS/United States