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.
Highlights
Smith-Magenis syndrome (SMS, MIM 182290) is a rare multiple congenital anomaly and developmental disability syndrome with an estimated incidence of 1:15,000–1:25,000 live births [1].The syndrome is commonly characterized by a specific combination of clinical features, including distinctive craniofacial appearances, skeletal anomalies, speech and motor delay, a variable degreeBiology 2018, 7, 31; doi:10.3390/biology7020031 www.mdpi.com/journal/biologyBiology 2018, 7, 31 of intellectual disability, sleep disturbances, and self-injurious and/or aggressive attention-seeking behavior [1,2].Autism spectrum disorder (ASD) is characterized by significant deficits in reciprocal social interactions, impaired communication and restricted, repetitive behaviors
The Retinoic Acid Induced 1 (RAI1) gene alteration is predicted to result in an amino acid change from an arginine to a glutamine at position 1147 (p.R1147Q)
= 0.6), indicating the mutated proteins the comparable transcription synthesis, subcellular localization, transcription activity of thehad. These results indicated thatorthe p.R1147Q factor variant apparently effect on the synthesis, we tested the capacity of the mutant form in recognizing and activating the transcription subcellular localization, or transcription factor activity of the RAI1 protein
Summary
Smith-Magenis syndrome (SMS, MIM 182290) is a rare multiple congenital anomaly and developmental disability syndrome with an estimated incidence of 1:15,000–1:25,000 live births [1]. Autism spectrum disorder (ASD) is characterized by significant deficits in reciprocal social interactions, impaired communication and restricted, repetitive behaviors. Mice carrying an inactivated Rai allele (Rai1+/− ) showed most of the SMS features and showed diminished interest in social odors, abnormal submissive tendencies, and increased repetitive behaviors suggesting a role of Rai in social behavior in mice [17,18,19]. Findings of aberrant social behaviors in mice carrying deletions or duplications of multiple genes, including the Rai gene, need to be interpreted with caution [20]
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