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
Affiliations
Clemer Abad
John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA
Melissa M. Cook
J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA
Lei Cao
John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA
Julie R. Jones
Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA
Nalini R. Rao
John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA
Lynn Dukes-Rimsky
J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA
Rini Pauly
J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA
Cindy Skinner
J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA
Yunsheng Wang
School of Computing, Clemson University, Clemson, SC 29634, USA
Feng Luo
School of Computing, Clemson University, Clemson, SC 29634, USA
Roger E. Stevenson
J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA
Katherina Walz
John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA
Anand K. Srivastava
J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA
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.
