A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation
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 functi...
Main Authors: | , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2018-05-01
|
Series: | Biology |
Subjects: | |
Online Access: | http://www.mdpi.com/2079-7737/7/2/31 |
id |
doaj-47129db58e4140aa86f110905720e447 |
---|---|
record_format |
Article |
spelling |
doaj-47129db58e4140aa86f110905720e4472020-11-24T21:08:01ZengMDPI AGBiology2079-77372018-05-01723110.3390/biology7020031biology7020031A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome PresentationClemer Abad0Melissa M. Cook1Lei Cao2Julie R. Jones3Nalini R. Rao4Lynn Dukes-Rimsky5Rini Pauly6Cindy Skinner7Yunsheng Wang8Feng Luo9Roger E. Stevenson10Katherina Walz11Anand K. Srivastava12John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USAJ. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USAJohn P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USAMolecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USAJohn P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USAJ. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USAJ. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USAJ. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USASchool of Computing, Clemson University, Clemson, SC 29634, USASchool of Computing, Clemson University, Clemson, SC 29634, USAJ. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USAJohn P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USAJ. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USADeletions 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.http://www.mdpi.com/2079-7737/7/2/31autism spectrum disorderSmith-Magenis syndromeRAI1neurodevelopmental disordermutation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation Biology autism spectrum disorder Smith-Magenis syndrome RAI1 neurodevelopmental disorder mutation |
author_facet |
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 |
author_sort |
Clemer Abad |
title |
A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation |
title_short |
A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation |
title_full |
A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation |
title_fullStr |
A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation |
title_full_unstemmed |
A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation |
title_sort |
rare de novo rai1 gene mutation affecting bdnf-enhancer-driven transcription activity associated with autism and atypical smith-magenis syndrome presentation |
publisher |
MDPI AG |
series |
Biology |
issn |
2079-7737 |
publishDate |
2018-05-01 |
description |
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. |
topic |
autism spectrum disorder Smith-Magenis syndrome RAI1 neurodevelopmental disorder mutation |
url |
http://www.mdpi.com/2079-7737/7/2/31 |
work_keys_str_mv |
AT clemerabad araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT melissamcook araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT leicao araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT julierjones araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT nalinirrao araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT lynndukesrimsky araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT rinipauly araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT cindyskinner araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT yunshengwang araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT fengluo araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT rogerestevenson araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT katherinawalz araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT anandksrivastava araredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT clemerabad raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT melissamcook raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT leicao raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT julierjones raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT nalinirrao raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT lynndukesrimsky raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT rinipauly raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT cindyskinner raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT yunshengwang raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT fengluo raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT rogerestevenson raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT katherinawalz raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation AT anandksrivastava raredenovorai1genemutationaffectingbdnfenhancerdriventranscriptionactivityassociatedwithautismandatypicalsmithmagenissyndromepresentation |
_version_ |
1716761183158009856 |