Ozzy, a Jag1 vestibular mouse mutant, displays characteristics of Alagille syndrome

Neurobiology of Disease

Viviane Van Hoof¹  An Zwijsen²  Luk Cox²  Sofie Thys³  Lut Van Laer³  Guy Van Camp³  Karen Vrijens³  Marcel T. De Jeu⁴  Chris I. De Zeeuw⁴  Andrei A. Postnov⁵  Nora M. De Clerck⁵  Marcus Mueller⁶  Markus Pfister⁶ 

[1] Department of Clinical Chemistry, University Hospital Antwerp, B-2650 Edegem, Belgium;Department of Developmental Biology (VIB 7), Flanders Interuniversity Institute for Biotechnology (VIB), and Laboratory of Molecular Biology (CELGEN), University of Leuven, B-3000 Leuven, Belgium;Department of Medical Genetics, University of Antwerp, B-2610 Antwerp, Belgium;Department of Neuroscience, Erasmus MC, 3015 GE Rotterdam, The Netherlands;Department of Physics, Department of Biomedical Sciences, University of Antwerp, B-2020 Antwerp, Belgium;HNO-Universitätsklinik, Universität Tübingen, D-72074 Tübingen, Germany;

关键词: Vestibular dysfunction;    Vestibulo-ocular reflex;    Optokinetic reflex;    Micro-CT scanning;    Mouse model;    Jagged1;   

DOI  :  

来源: DOAJ

【 摘 要 】

The mouse mutant Ozzy, originating from an ENU-mutagenesis programme, displays a head bobbing phenotype. We report here that Ozzy mice show a clear deficit in vestibulo-ocular reflex (VOR). Micro-CT scanning of the inner ears showed narrowing and truncations of at least one of the semicircular canals and loss of the ampullae. Frequency-specific auditory-evoked brainstem response (ABR) tests revealed a slight threshold increase in the middle frequency range compared to wild-type littermates. Linkage analysis localised the gene in a 5.5-cM region on chromosome 2. Subsequently, a 499 T→A missense mutation was identified in Jag1, leading to a substitution of an evolutionary conserved tryptophane (W167R). Mutations in the human homologue of Jag1 cause Alagille syndrome (AGS), an autosomal dominant disorder associated with liver, heart, eye and skeletal abnormalities, accompanied by a characteristic facies. In human patients, it occasionally affects other organ systems like the kidney or the inner ear. Liver disease is the main diagnostic factor for AGS. Ozzy mice showed significantly less intrahepatic bile ducts than wild-type littermates. Thirty-seven percent of Ozzy mice showed heart defects. No eye or vertebral abnormalities could be detected. In conclusion, Ozzy mice show two of the major and one minor characteristic of AGS.

【 授权许可】

Unknown