The RAI1gene is located on chromosome 17p11.2. It has six exons, and four exons encode a protein with 1906 amino acids. RAI1 is a nuclear chromatin-binding protein with several functional domains, including a polymorphic polyglutamine repeat domain (Poly-Q), polyserine-rich domains (Poly-S1 & S2), bipartite localization signals (NLS1 and NLS2), , and a plant homeodomain (PHD).
Although RAI1is expressed at low levels in most all tissues, it is more highly expressed in neuronal tissues. Basic research is focused toward understanding the function of RAI1. Current studies describe RAI1 as a transcription factor related to embryonic neurodevelopment and neuronal differentiation, cell growth and cell cycle regulation, lipid and glucose metabolism, bone and skeletal development, behavioural functions, and circadian activity.
RAI1is a dosage-sensitive gene in a repeat-rich region of chromosome 17p11.2. Genomic instability due to the presence of low-copy repetitive elements, which lead to a predisposition for the occurrence of non-allelic recombination (NAHR) and non-homologous end joining (NHEJ). Such recombination can result in deletions or duplications. Potocki-Lupski syndrome (PTLS; OMIM #610883) is the result of duplication in the region. Smith-Magenis syndrome (SMS; OMIM #182290) can occur when there is a deletion involving the gene or due to mutation of the RAI1gene. Pathogenic variants in RAI1have been identified that result in haploinsufficiency and lead to SMS. These pathogenic variants are typically single nucleotide variants or small indels that result in nonsense or frameshift effects and are primarily observed in exon 3, which encodes most of the protein.
To perform laboratory diagnosis for SMS or PTLS, different techniques can be used, such as fluorescent in situ hybridization (FISH) using an RAI1-specific probe, multiple ligation-dependent probe amplification (MLPA), quantitative real-time PCR (qPCR), or chromosomal microarrays (CMA) to identify copy number variations (CNV). For individuals without a CNV, RAI1gene sequencing or exome or genome sequencing should be performed to detect pathogenic variants.
RAI1is conserved across vertebrate species, and this homology has allowed several studies to be carried out in mice. Mouse models of SMS, whether chromosomal deletion or only Rai1targeted loss of function, had craniofacial alterations, behavioral and developmental anomalies, and obesity, similar to people with SMS. In the Rai1duplication models, mice exhibited lean body mass hyperkinetic behavior, poor maternal skills, and other mild neurological deficits often seen in people with PTLS.
RAI1 Potocki-Lupski Syndrome