title: Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2).
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.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Katherina
authors.initials: K
authors.lastname: Walz
authors.forename: Richard
authors.initials: R
authors.lastname: Paylor
authors.forename: Jiong
authors.initials: J
authors.lastname: Yan
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D020440:Gene Duplication; D014644:Genetic Variation / Q000235:genetics; D016678:Genome / Q000235:genetics; D007858:Learning; D008297:Male; D008568:Memory; D051379:Mice; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*
chemical_list: C502844:Rai1 protein, mouse; D015534:Trans-Activators