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Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2)
Katherina Walz, … , Weimin Bi, James R. Lupski
Katherina Walz, … , Weimin Bi, James R. Lupski
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):3035-3041. https://doi.org/10.1172/JCI28953.
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Research Article Genetics

Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2)

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Abstract

Genomic disorders are conditions that result from DNA rearrangements, such as deletions or duplications. The identification of the dosage-sensitive gene(s) within the rearranged genomic interval is important for the elucidation of genes responsible for complex neurobehavioral phenotypes. Smith-Magenis syndrome is associated with a 3.7-Mb deletion in 17p11.2, and its clinical presentation is caused by retinoic acid inducible 1 (RAI1) haploinsufficiency. The reciprocal microduplication syndrome, dup(17)(p11.2p11.2), manifests several neurobehavioral abnormalities, but the responsible dosage-sensitive gene(s) remain undefined. We previously generated a mouse model for dup(17)(p11.2p11.2), Dp(11)17/+, that recapitulated most of the phenotypes observed in human patients. We have now analyzed compound heterozygous mice carrying a duplication [Dp(11)17] in one chromosome 11 along with a null allele of Rai1 in the other chromosome 11 homologue [Dp(11)17/Rai1– mice] in order to study the relationship between Rai1 gene copy number and the Dp(11)17/+ phenotypes. Normal disomic Rai1 gene dosage was sufficient to rescue the complex physical and behavioral phenotypes observed in Dp(11)17/+ mice, despite altered trisomic copy number of the other 18 genes present in the rearranged genomic interval. These data provide a model for variation in copy number of single genes that could influence common traits such as obesity and behavior.

Authors

Katherina Walz, Richard Paylor, Jiong Yan, Weimin Bi, James R. Lupski

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Figure 1

Representation of the genomic region duplicated in Dp(11)17.

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Representation of the genomic region duplicated in Dp(11)17.
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A schematic representation of the 17p11.2 region of human chromosome 17 and the 32- to 34-cM interval of the syntenic region of mouse chromosome 11 is shown. The gray circles depict the centromeres. The horizontal black line (bottom) denotes the genomic interval encompassing the Dp(11)17 duplication generated by chromosomal engineering. 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). The mouse Rai1 and human RAI1 genes are indicated in boxes.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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