Abstract
Each human's genome is distinguished by extra and missing DNA that can be “benign” or powerfully impact everything from development to disease. In the case of genomic disorders DNA rearrangements, such as deletions or duplications, correlate with a clinical specific phenotype. The clinical presentations of genomic disorders were thought to result from altered gene copy number of physically linked dosage sensitive genes. Genomic disorders are frequent diseases (~1 per 1,000 births). Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are genomic disorders, associated with a deletion and a duplication, of 3.7 Mb respectively, within chromosome 17 band p11.2. This region includes 23 genes. Both syndromes have complex and distinctive phenotypes including multiple congenital and neurobehavioral abnormalities. Human chromosome 17p11.2 is syntenic to the 32-34 cM region of murine chromosome 11. The number and order of the genes are highly conserved. In this review, we will exemplify how genomic disorders can be modeled in mice and the advantages that such models can give in the study of genomic disorders in particular and gene copy number variation (CNV) in general. The contributions of the SMS and PTLS animal models in several aspects ranging from more specific ones, as the definition of the clinical aspects of the human clinical spectrum, the identification of dosage sensitive genes related to the human syndromes, to the more general contributions as the definition of genetic locus impacting obesity and behavior and the elucidation of general mechanisms related to the pathogenesis of gene CNV are discussed.
Highlights
Genomic structural changes, such as gene Copy Number Variations (CNVs) are extremely abundant among phenotypically normal human individuals [1, 2]
CNV are present in a large proportion of the human genome and include hundreds of genes [3]
Genomic disorders are the pathological evidence of CNV and they are frequent conditions, ~1 per 1,000 births [14]
Summary
Genomic structural changes, such as gene Copy Number Variations (CNVs) are extremely abundant among phenotypically normal human individuals [1, 2]. Over 19,000 human CNVs from approximately 6,200 regions (CNVRs) have been identified, ranging from 1kb to several megabases in size (http:// projects.tcag.ca/variation/) They are recognized important mutational mechanisms involved in several phenotypes that range from “normal” variability between individuals, susceptibility to traits, genome evolution, to specific human genomic disorders [4,5,6,7,8,9,10,11,12,13]. Extensive studies have identified several CGS and despite the intra-patient variability, each CGS is defined by specific and complex phenotypes that can include neurobehavioral traits and congenital abnormalities [15,16,17,18] among other clinical presentations. The dosage sensitive gene(s) responsible for PTLS remains unidentified; it was possible to demonstrate that CNV of the Rai gene is mostly responsible for complex physical and behavioral traits in a mouse model for PTLS [53]
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