Relevance to Autism

Smith-Magenis syndrome is caused either by large interstitial deletions in the 17p11.2 chromosomal region (Smith et al., 1986) or by mutations in the RAI1 gene (Slager et al., 2003), which is located within the Smith-Magenis chromosomal region. Conversely, Potocki-Lupski syndrome is caused by duplications of the same 17p11.2 chromosomal region (Potocki et al., 2007). Both syndromes share overlapping clinical features, including behavioral problems such as autistic features. RAI1 was included within a 17p11.2 duplication identified in an individual with autism and intellectual disability and showed altered gene expression (Nakamine et al., 2008); it was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. A de novo frameshift variant was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo missense variants (one of which was predicted to be damaging in silico) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). A de novo protein-truncating variant in RAI1 was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; three protein-truncating variants in this gene were also observed in case samples from the Danish iPSYCH study in this report. Furthermore, TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified RAI1 as a candidate gene with a false discovery rate (FDR) 0.01. A de novo missense variant in the RAI1 gene that was experimentally shown to significantly reduce BDNF-enhancer-driven transcription activity was identified in a male patient diagnosed with ASD and displaying an atypical Smith-Magenis syndrome presentation in Abad et al., 2018. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified RAI1 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

Transcriptional regulator of the circadian clock components: CLOCK, BMAL1, BMAL2, PER1/3, CRY1/2, NR1D1/2 and RORA/C. Positively regulates the transcriptional activity of CLOCK a core component of the circadian clock. Regulates transcription through chromatin remodeling by interacting with other proteins in chromatin as well as proteins in the basic transcriptional machinery. May be important for embryonic and postnatal development. May be involved in neuronal differentiation.

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Model Summary

Rai1 haploinsufficiency is responsible for obesity and craniofacial phenotypes in mice with Smith Magenis Syndrome deletions, and indicate Rai1 is important for embryonic and postnatal developments.

References