title: A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect.
abstract: Familial dysautonomia (FD) is a severe hereditary sensory and autonomic neuropathy, and all patients with FD have a splice mutation in the IKBKAP gene. The FD splice mutation results in variable, tissue-specific skipping of exon 20 in IKBKAP mRNA, which leads to reduced IKAP protein levels. The development of therapies for FD will require suitable mouse models for preclinical studies. In this study, we report the generation and characterization of a mouse model carrying the complete human IKBKAP locus with the FD IVS20+6T-->C splice mutation. We show that the mutant IKBKAP transgene is misspliced in this model in a tissue-specific manner that replicates the pattern seen in FD patient tissues. Creation of this humanized mouse is the first step toward development of a complex phenotypic model of FD. These transgenic mice are an ideal model system for testing the effectiveness of therapeutic agents that target the missplicing defect. Last, these mice will permit direct studies of tissue-specific splicing and the identification of regulatory factors that play a role in complex gene expression.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hims
authors.forename: Ranjit S
authors.initials: RS
authors.lastname: Shetty
authors.forename: James
authors.initials: J
authors.lastname: Pickel
authors.forename: James
authors.initials: J
authors.lastname: Mull
authors.forename: Maire
authors.initials: M
authors.lastname: Leyne
authors.forename: Lijuan
authors.initials: L
authors.lastname: Liu
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Susan A
authors.initials: SA
authors.lastname: Slaugenhaupt
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004402:Dysautonomia, Familial / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D011995:Recombination, Genetic; D014018:Tissue Distribution; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; C491968:Ikbkap protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D035602:Transcriptional Elongation Factors