title: Disruption of the mouse Jhy gene causes abnormal ciliary microtubule patterning and juvenile hydrocephalus.
abstract: Congenital hydrocephalus, the accumulation of excess cerebrospinal fluid (CSF) in the ventricles of the brain, affects one of every 1000 children born today, making it one of the most common human developmental disorders. Genetic causes of hydrocephalus are poorly understood in humans, but animal models suggest a broad genetic program underlying the regulation of CSF balance. In this study, the random integration of a transgene into the mouse genome led to the development of an early onset and rapidly progressive hydrocephalus. Juvenile hydrocephalus transgenic mice (Jhy(lacZ)) inherit communicating hydrocephalus in an autosomal recessive fashion with dilation of the lateral ventricles observed as early as postnatal day 1.5. Ventricular dilation increases in severity over time, becoming fatal at 4-8 weeks of age. The ependymal cilia lining the lateral ventricles are morphologically abnormal and reduced in number in Jhy(lacZ/lacZ) brains, and ultrastructural analysis revealed disorganization of the expected 9+2 microtubule pattern. Rather, the majority of Jhy(lacZ/lacZ) cilia develop axonemes with 9+0 or 8+2 microtubule structures. Disruption of an unstudied gene, 4931429I11Rik (now named Jhy) appears to underlie the hydrocephalus of Jhy(lacZ/lacZ) mice, and the Jhy transcript and protein are decreased in Jhy(lacZ/lacZ) mice. Partial phenotypic rescue was achieved in Jhy(lacZ/lacZ) mice by the introduction of a bacterial artificial chromosome (BAC) carrying 60-70% of the JHY protein coding sequence. Jhy is evolutionarily conserved from humans to basal vertebrates, but the predicted JHY protein lacks identifiable functional domains. Ongoing studies are directed at uncovering the physiological function of JHY and its role in CSF homeostasis.
authors.affiliation: Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors.forename: Oliver K
authors.initials: OK
authors.lastname: Appelbe
authors.forename: Bryan
authors.initials: B
authors.lastname: Bollman
authors.forename: Ali
authors.initials: A
authors.lastname: Attarwala
authors.forename: Lindy A
authors.initials: LA
authors.lastname: Triebes
authors.forename: Hilmarie
authors.initials: H
authors.lastname: Muniz-Talavera
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Curry
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Schmidt
mesh_terms: D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002555:Cerebrospinal Fluid / Q000378:metabolism; D002923:Cilia / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D018450:Disease Progression; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004805:Ependyma / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017353:Gene Deletion; D017930:Genes, Reporter; D006801:Humans; D006849:Hydrocephalus / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D010641:Phenotype; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D019076:Transgenes / Q000235:genetics
chemical_list: D011506:Proteins; D012333:RNA, Messenger; C400784:Tex21 protein, mouse
keywords: 4931429I11Rik; Cilia; Hydrocephalus; Jhy; Mouse
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