Ozzy, a Jag1 vestibular mouse mutant, displays characteristics of Alagille syndrome.
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.
Vrijens
Karen
K
Department of Medical Genetics, University of Antwerp, B-2610 Antwerp, Belgium.
Thys
Sofie
S
De Jeu
Marcel T
MT
Postnov
Andrei A
AA
Pfister
Markus
M
Cox
Luk
L
Zwijsen
An
A
Van Hoof
Viviane
V
Mueller
Marcus
M
De Clerck
Nora M
NM
De Zeeuw
Chris I
CI
Van Camp
Guy
G
Van Laer
Lut
L
D016738:Alagille Syndrome / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*; D000818:Animals; D001847:Bone Diseases / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D003051:Cochlea / Q000473:pathology / Q000502:physiology; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics / Q000502:physiology; D008040:Genetic Linkage; D006130:Growth Disorders / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072100:Jagged-1 Protein; D037102:Lectins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008818:Mice, Neurologic Mutants / Q000502:physiology*; D008855:Microscopy, Electron, Scanning; D020125:Mutation, Missense / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D012027:Reflex, Vestibulo-Ocular / Q000235:genetics / Q000502:physiology; D000072099:Serrate-Jagged Proteins; D014057:Tomography, X-Ray Computed; D014722:Vestibule, Labyrinth / Q000502:physiology*; D014786:Vision Disorders / Q000235:genetics; D014796:Visual Perception
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D037102:Lectins; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D004247:DNA