title: The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: positional complementation cloning and extragenic suppression.
abstract: The mouse vibrator mutation causes an early-onset progressive action tremor, degeneration of brain stem and spinal cord neurons, and juvenile death. We cloned the vibrator mutation using an in vivo positional complementation approach and complete resequencing of the resulting 76 kb critical region from vibrator and its parental chromosome. The mutation is an intracisternal A particle retroposon insertion in intron 4 of the phosphatidylinositol transfer protein alpha gene, causing a 5-fold reduction in RNA and protein levels. Expression of neurofilament light chain is also reduced in vibrator, suggesting one signaling pathway that may underlie vibrator pathology. The vibrator phenotype is suppressed in one intercross. We performed a complete genome scan and mapped a major suppressor locus (Mvb-1) to proximal chromosome 19.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Hamilton
authors.forename: D J
authors.initials: DJ
authors.lastname: Smith
authors.forename: K L
authors.initials: KL
authors.lastname: Mueller
authors.forename: A W
authors.initials: AW
authors.lastname: Kerrebrock
authors.forename: R T
authors.initials: RT
authors.lastname: Bronson
authors.forename: V
authors.initials: V
authors.lastname: van Berkel
authors.forename: M J
authors.initials: MJ
authors.lastname: Daly
authors.forename: L
authors.initials: L
authors.lastname: Kruglyak
authors.forename: M P
authors.initials: MP
authors.lastname: Reeve
authors.forename: J L
authors.initials: JL
authors.lastname: Nemhauser
authors.forename: T L
authors.initials: TL
authors.lastname: Hawkins
authors.forename: E M
authors.initials: EM
authors.lastname: Rubin
authors.forename: E S
authors.initials: ES
authors.lastname: Lander
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001284:Atrophy; D001933:Brain Stem / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005816:Genetic Complementation Test; D016678:Genome; D006720:Homozygote; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008818:Mice, Neurologic Mutants / Q000235:genetics*; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000235:genetics*; D009422:Nervous System Diseases / Q000235:genetics / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D016366:Open Reading Frames / Q000235:genetics; D010716:Phosphatidylinositols / Q000378:metabolism; D049294:Phospholipid Transfer Proteins; D017422:Sequence Analysis, DNA; D013116:Spinal Cord / Q000737:chemistry / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D016900:Neurofilament Proteins; D010716:Phosphatidylinositols; D049294:Phospholipid Transfer Proteins; C044882:neurofilament protein L