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.
Highlights
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 associated with abnormal phenotypic outcomes [3,4,5,6,7]
There is a great level of complexity between the presence of CNV and the resulting phenotypes that is a direct consequence of specific altered gene dosage
Summary
Genomic structural changes, such as gene Copy Number Variations (CNVs) are extremely abundant in the human genome. There are two cases of patients with SMS that carry missense mutations that alter amino acids within a highly conserved region of the gene (A4685G and G5423A) Both patients have a wide spectrum of neurobehavioral phenotypes, including sleep disturbance, self-injurious behaviors, mental retardation and developmental delay. This supports the fact that RAI1 is a protein directly involved in these specific neurobehavioral phenotypes, since the point mutations mentioned above generate a full length protein with only the change of one single amino acid, with stability similar to the wild type protein [34]. A recent report showed a patient with PTLS phenotype having a duplication of a very small region that only contains the RAI1 gene [29] This is consistent with the notion of RAI1 as the dosage sensitive gene within this genomic region (Table 1). A strategy developed to introduce defined chromosomal rearrangements into the mouse genome to delineate gene haploinsufficiency effects (haploid genetics) [39,40,41,42,43], a deletion and reciprocal duplication in the mouse chromosome region syntenic to the SMS critical in-
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