Mouse models of genomic syndromes as tools for understanding the basis of complex traits: an example with the smith-magenis and the potocki-lupski syndromes

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.

Keywords: Gene copy number variation; complex traits; mouse models.; phenotypic consequences.

Fig. (1).

Steps to consider when modeling genomic disorders in mice. A graphic representation of the steps to follow when deciding to generate a mouse model for CGS is presented. Different strategies could be followed depending if the dosage sensitive gene is known or unknown. Multiple advantages can be obtained with the different models as listed in the figure.

Fig. (2).

Schematic representation of the SMS and PTLS genomic region. Representation of the 17p11.2 region of human chromosome 17 and its syntenic counterpart region 32- to 34-cM of the mouse chromosome 11 is depicted [53]. Centromeres are represented in gray circles. Note that the numbers, orientations, and relative orders of the genes in these syntenic genomic intervals are extremely conserved. Three low-copy repeats are present in the human region: SMS-REPD (distal); SMS-REPM (middle); SMS-REPP (proximal).

Fig. (3).

Existing mouse models of SMS and PTLS syndromes. A) Schematic representation of the wild type 32-34 cM region of 11 mouse chromosome (black line, Mouse 32-34 cM) and the different deletions available at the present (black-grey doted line). The SMS critical region (Df(11)17) [65] and the smaller deletions (Df(11)17-1, -2, -3) [67] are depicted. Finally the mouse harboring a LacZ knock-in in the Rai1 coding sequence is illustrated with a light grey triangle (LacZ knock-in) [68]. B) Representation of the two murine models for the PTLS, one carrying the duplication of the SMS critical region in 11 chromosome 32-34 cM (dark grey line)[65] and a BAC transgenic mouse containing the Rai1 gene [69]. The sizes of the rearrangements are specified within parenthesis.

Fig. (4).

Contribution of existing mouse models for SMS and PTLS. The contribution of the study of the existing SMS and PTLS mouse models in the understanding of the phenotypic and molecular consequences of genomic disorders.