title: Mice Haploinsufficient for Ets1 and Fli1 Display Middle Ear Abnormalities and Model Aspects of Jacobsen Syndrome.
abstract: E26 transformation-specific 1 (ETS1) and friend leukemia integration 1 (FLI1) are members of the ETS family of transcription factors, of which there are 28 in humans. Both genes are hemizygous in Jacobsen syndrome, an 11q contiguous gene deletion disorder involving thrombocytopenia, facial dysmorphism, growth and mental retardation, malformation of the heart and other organs, and hearing impairment associated with recurrent ear infections. To determine whether any of these defects are because of hemizygosity for ETS1 and FLI1, we characterized the phenotype of mice heterozygous for mutant alleles of Ets1 and Fli1. Fli1(+/-) mice displayed mild thrombocytopenia, as did Ets1(+/-)Fli1(+/-) animals. Fli1(+/-) and Ets1(+/-)Fli1(+/-) mice also displayed craniofacial abnormalities, including a small middle ear cavity, short nasal bone, and malformed interface between the nasal bone process and cartilaginous nasal septum. They exhibited hearing impairment, otitis media, fusions of ossicles to the middle ear wall, and deformed stapes. Hearing impairment was more penetrant and stapes malformations were more severe in Ets1(+/-)Fli1(+/-) mice than in Fli1(+/-) mice, indicating partial functional redundancy of these transcription factors during auditory development. Our findings indicate that the short nose, otitis media, and hearing impairment in Jacobsen syndrome are likely because of hemizygosity for ETS1 and FLI1.
authors.affiliation: Murdoch Childrens Research Institute, Parkville, Victoria, Australia; HEARing Cooperative Research Centre, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Marina R
authors.initials: MR
authors.lastname: Carpinelli
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kruse
authors.affiliation: Department of Physics, ARC Centre of Excellence for Coherent X-Ray Science, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Benedicta D
authors.initials: BD
authors.lastname: Arhatari
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Marlyse A
authors.initials: MA
authors.lastname: Debrincat
authors.affiliation: Murdoch Childrens Research Institute, Parkville, Victoria, Australia; HEARing Cooperative Research Centre, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Ogier
authors.affiliation: INSERM UMR 1126 Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bories
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: Murdoch Childrens Research Institute, Parkville, Victoria, Australia; HEARing Cooperative Research Centre, University of Melbourne, Melbourne, Victoria, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Genetics, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: rachel.burt@mcri.edu.au.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Burt
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004432:Ear, Middle / Q000002:abnormalities; D005260:Female; D005838:Genotype; D057895:Haploinsufficiency; D034381:Hearing Loss / Q000235:genetics; D006801:Humans; D054868:Jacobsen Distal 11q Deletion Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice / Q000002:abnormalities / Q000235:genetics; D009295:Nasal Bone / Q000002:abnormalities; D010033:Otitis Media / Q000235:genetics; D010641:Phenotype; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics*
chemical_list: C494042:Ets1 protein, mouse; C497426:Fli1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D051789:Proto-Oncogene Protein c-fli-1