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, 11 (8), 607-17

Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior

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Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior

Paulina Carmona-Mora et al. Curr Genomics.

Abstract

Genomic structural changes, such as gene Copy Number Variations (CNVs) are extremely abundant in the human genome. An enormous effort is currently ongoing to recognize and catalogue human CNVs and their associations with abnormal phenotypic outcomes. Recently, several reports related neuropsychiatric diseases (i.e. autism spectrum disorders, schizophrenia, mental retardation, behavioral problems, epilepsy) with specific CNV. Moreover, for some conditions, both the deletion and duplication of the same genomic segment are related to the phenotype. Syndromes associated with CNVs (microdeletion and microduplication) have long been known to display specific neurobehavioral traits. It is important to note that not every gene is susceptible to gene dosage changes and there are only a few dosage sensitive genes. Smith-Magenis (SMS) and Potocki-Lupski (PTLS) syndromes are associated with a reciprocal microdeletion and microduplication within chromosome 17p11.2. in humans. The dosage sensitive gene responsible for most phenotypes in SMS has been identified: the Retinoic Acid Induced 1 (RAI1). Studies on mouse models and humans suggest that RAI1 is likely the dosage sensitive gene responsible for clinical features in PTLS. In addition, the human RAI1 gene has been implicated in several neurobehavioral traits as spinocerebellar ataxia (SCA2), schizophrenia and non syndromic autism. In this review we discuss the evidence of RAI1 as a dosage sensitive gene, its relationship with different neurobehavioral traits, gene structure and mutations, and what is known about its molecular and cellular function, as a first step in the elucidation of the mechanisms that relate dosage sensitive genes with abnormal neurobehavioral outcomes.

Keywords: Copy Number Variation; Potocki-Lupski Syndrome; RAI1; Smith-Magenis Syndrome; dosage sensitive gene; neurobehavioral traits; transcription factor activity..

Figures

Fig. (1)
Fig. (1)
Structure of RAI1. By in silico analyses, several domains have been found for RAI1: a polyglutamine tract at the N-terminal of the protein, two polyserine domains, a PHD domain at the C-terminal of RAI1 and two putative nuclear localization signals (NLS). RAI1 protein structure is schematically represented, and the domains described are showed with their localization in the amino acidic sequence. By the evaluation of the wild type and mutant proteins associated to SMS, two main domains were found: the N-terminal half of RAI1 is responsible for the transactivational activity and C-terminal half beginning in residue 1038 is responsible for nuclear localization [34]. The RAI1 PTMs found are depicted with black figures while the putative sites are represented by white figures. The phosphorylation sites (1Thr and 13Ser) found in HeLa cells are represented with black circles. The reported acetylation site is depicted with a black diamond. The putative SUMOylation site with the highest score is represented with a white triangle. Below, the other four isoforms described for human RAI1 are represented. These isoforms differ from the canonical one by the change of several residues (depicted in slanted rectangles) and also by some fragments missed (depicted by discontinued lines). Isoform 2 is the most similar to the canonical, while in isoform 3 are missing the second polyserine tract and PHD domain. Isoform 4 is the shortest containing only the first half of RAI1 protein, not encompassing NLSs and being comparable to the truncated proteins found in some SMS patients. The longest variant of RAI1 (ENSP00000379122) is a protein reported by the online database of eukaryotic genomes, Ensembl, which has a length of 1993 amino acids and has complete homology with the isoform 1 until amino acid 1855.
Fig. (2)
Fig. (2)
RAI1 changes associated with neurobehavioral phenotypes. The traits that have been found related to RAI1 CNVs, mutations or sequence changes are summarized. There are phenotypes that are associated with only one copy of RAI1 gene (SMS). Many of these phenotypes are also related to carrying two copies of the gene, but one allele with mutations (SMS caused by frameshifts, nonsense or missense mutations) (a). Harboring two copies of RAI1 gene but with polymorphic CAG repeats influence other neurobehavioral traits (b). The alteration of RAI1 dosage to three copies causes specific phenotypes of PTLS as well as features that overlap with some clinical characteristics of SMS.

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References

    1. Iafrate A J, Feuk L, Rivera M N, Listewnik M L, Donahoe P K, Qi Y, Scherer S W, Lee C. Detection of large-scale variation in the human genome. Nat. Genet. 2004;36:949–951. - PubMed
    1. Conrad D F, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, Aerts J, Andrews T D, Barnes C, Campbell P, Fitz-gerald T, Hu M, Ihm C H, Kristiansson K, Macarthur D G, Macdonald J R, Onyiah I, Pang A W, Robson S, Stirrups K, Valsesia A, Walter K, Wei J, Tyler-Smith C, Carter N P, Lee C, Scherer S W, Hurles M E. The Wellcome Trust Case Control Consortium; Origins and functional impact of copy number variation in the human genome. Nature. 2009;464:704–712. - PMC - PubMed
    1. Beckmann J S, Estivill X, Antonarakis S E. Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nat. Rev. Genet. 2007;8:639–646. - PubMed
    1. Redon R, Ishikawa S, Fitch K R, Feuk L, Perry G H, Andrews T D, Fiegler H, Shapero M H, Carson A R, Chen W, Cho E K, Dallaire S, Freeman J L, Gonzalez J R, Gra-tacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald J R, Marshall C R, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville M J, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad D F, Estivill X, Tyler-Smith C, Carter N P, Abu-ratani H, Lee C, Jones K W, Scherer S W, Hurles M E. Global variation in copy number in the human genome. Nature. 2006;444:444–454. - PMC - PubMed
    1. Korn J M, Kuruvilla F G, McCarroll S A, Wysoker A, Nemesh J, Cawley S, Hubbell E, Veitch J, Collins P J, Dar-vishi K, Lee C, Nizzari M M, Gabriel S B, Purcell S, Daly M J, Altshuler D. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat. Genet. 2008;40:1253–1260. - PMC - PubMed

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