title: Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia.
abstract: Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Δ20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Δ20/flox)). The TgFD9; Ikbkap(Δ20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect.
authors.affiliation: Center for Human Genetic Research.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Morini
authors.affiliation: Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN 38163, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Dietrich
authors.affiliation: Center for Human Genetic Research.
authors.forename: Monica
authors.initials: M
authors.lastname: Salani
authors.affiliation: Nerve Unit, Departments of Neurology and Pathology (Neuropathology) and.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Downs
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA and.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wojtkiewicz
authors.affiliation: Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN 38163, USA.
authors.forename: Shanta
authors.initials: S
authors.lastname: Alli
authors.affiliation: Center for Human Genetic Research.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brenner
authors.affiliation: Center for Human Genetic Research.
authors.forename: Mats
authors.initials: M
authors.lastname: Nilbratt
authors.affiliation: Center for Human Genetic Research.
authors.forename: John W
authors.initials: JW
authors.lastname: LeClair
authors.affiliation: Nerve Unit, Departments of Neurology and Pathology (Neuropathology) and.
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Oaklander
authors.affiliation: Center for Human Genetic Research, idragatsis@uthsc.edu slaugenhaupt@chgr.mgh.harvard.edu.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Slaugenhaupt
authors.affiliation: Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN 38163, USA idragatsis@uthsc.edu slaugenhaupt@chgr.mgh.harvard.edu.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dragatsis
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017776:Autonomic Pathways / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004402:Dysautonomia, Familial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005091:Exons; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C491968:Ikbkap protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger