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, dosage sensitive gene, neurobehavioral traits, Potocki-Lupski Syndrome, RAI1, Smith- Magenis Syndrome, transcription factor activity, CNVs, PTLS, Acid Induced 1, spinocerebellar ataxia, SCA2, Smith-Magenis Syndrome, Contiguous Gene Syndromes, CGS, hemizygotes, missense alleles, nuclear localization signals, NLSs, plant homeo domain, PHD, -N-acetylglucosamine, O-GlcNac, Lysine acetylation, SUMOylation, Small Ubiquitin-like Modifier proteins, ZIC1, PSEN2, RXRB, CLN8, SCN12A, Ataxin 2, spinocerebellar ataxia type 2, CAG repeat polymorphism
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