Abstract
RAI1 (retinoic acid induced-1) is a dosage-sensitive gene that causes Smith-Magenis syndrome (SMS) when mutated or deleted and Potocki-Lupski Syndrome (PTLS) when duplicated, with psychiatric features commonly observed in both syndromes. How common genetic variants regulate this gene, however, is unknown. In this study, we found that RAI1 mRNA expression in Chinese prefrontal and temporal cortex correlate with genotypes of common single nucleotide polymorphisms (SNPs) located in the RAI1 5′-upstream region. Using genotype imputation, “R2-Δ2” analysis, and data from the RegulomeDB database, we identified SNPs rs4925102 and rs9907986 as possible regulatory variants, accounting for approximately 30–40% of the variance in RAI1 mRNA expression in both brain regions. Specifically, rs4925102 and rs9907986 are predicted to disrupt the binding of retinoic acid RXR-RAR receptors and the transcription factor DEAF1 (Deformed epidermal autoregulatory factor-1), respectively. Consistent with these predictions, we observed binding of RXRα and RARα to the predicted RAI1 target in chromatin immunoprecipitation assays. Retinoic acid is crucial for early development of the central neural system, and DEAF1 is associated with intellectual disability. The observation that a significant portion of RAI1 mRNA expression is genetically controlled raises the possibility that common RAI1 5′-region regulatory variants contribute more generally to psychiatric disorders.
Highlights
Retinoic acid induced 1 (RAI1) is a dose-sensitive gene located at Chr17p11.2, an unstable region subject to recurrent microdeletions, deletions, and duplications resulting from non-allelic homologous recombination (NAHR) between low-copy repeats (LCRs)[1]
To determine whether RAI1 mRNA expression is regulated by the same functional single nucleotide polymorphisms (SNPs) in the two brain regions, we investigated SNPs that are in linkage disequilibrium (LD) (Δ 2 > 0.5) with each of the three index SNPs in the prefrontal cortex or temporal cortex samples
We identified five SNPs located within the 5′ - upstream region of the human RAI1 gene with genotypes that correlate with RAI1 mRNA expression in Han Chinese samples of prefrontal cortex and temporal cortex
Summary
Retinoic acid induced 1 (RAI1) is a dose-sensitive gene located at Chr17p11.2, an unstable region subject to recurrent microdeletions, deletions, and duplications resulting from non-allelic homologous recombination (NAHR) between low-copy repeats (LCRs)[1]. The identification of rare nonsense and frameshift mutations in RAI1 that reproduce many of the features of SMS in the absence of Chr17p11.2 deletions, strongly implies that RAI1 haploinsufficiency is the primary cause of the syndrome[4,5]. This hypothesis is supported by murine models of SMS, where deletion of a 2 Mb region containing the murine Rai[1] gene[6,7] or targeted inactivation of the Rai[1] gene[8,9] reproduce many of the clinical phenotypes observed in SMS patients, including craniofacial abnormalities, seizures, abnormal circadian rhythm, and obesity. RAI1 mRNA has been detected in human frontal and temporal lobes by northern blot analysis[13]
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