The vibrator Mutation Causes Neurodegeneration via Reduced Expression of PITPα: Positional Complementation Cloning and Extragenic Suppression

Hamilton, Bruce A.; Smith, Desmond J.; Mueller, Kenneth L; Kerrebrock, Anne W.; Bronson, Roderick T.; Berkel, Victor van; Daly, Mark J.; Kruglyak, Leonid; Reeve, Mary Pat; Nemhauser, Jennifer L.; Hawkins, Trevor; Rubin, Edward M.; Lander, Eric S.

doi:10.1016/s0896-6273(00)80312-8

Cited by 179 publications

(107 citation statements)

References 47 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…Pups were screened for presence of the transgene by a competitive three-primer PCR assay using a forward primer corresponding to the cloning site of the vector at the 5′ end of the gene competing with a second forward primer outside the transgenic segment in the endogenous locus and a reverse primer in common to both transgenic and endogenous copies. Neither parental strain nor several derived hybrids has any observed vb-modifying effects in prior reports 3,32 or in non-transgenic littermates tested here. cochlea with only the basal turn.…”

Section: Transgenic Mouse Productioncontrasting

confidence: 64%

See 1 more Smart Citation

A natural allele of Nxf1 suppresses retrovirus insertional mutations

et al. 2003

Self Cite

View full text Add to dashboard Cite

Endogenous retroviruses have shaped the evolution of mammalian genomes. Host genes that control the effects of retrovirus insertions are therefore of great interest. The Modifier-of-vibrator-1 locus controls level of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the pitpn vb tremor mutation and the Eya1 BOR model of human branchiootorenal syndrome. Positional complementation cloning identifies Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between mRNA export receptor and pre-mRNA processing. Population structure of the suppressing allele in wild M. m. castaneus suggests selective advantage. A congenic Mvb1 CAST allele is a useful tool for modifying gene expression from existing mutations and could be used to manipulate engineered mutations containing retroviral elements.Mus musculus is a complex species group with subpopulations that have diverged and hybridized since becoming commensal with humans some 10,000 years ago. Allopatric divergence and re-hybridization of mouse lineages are thought to contribute to the diversity and activity of retroviral elements in the current mouse genomes 1,2 . Host genes that can NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript influence the expression of newly introduced (or newly mobilized) viral elements might be selected for variants that blunt these effects. Our results suggest that Mvb1 is such a locus.Mvb1 was originally identified as a strain-derived locus that modifies the neurological mutant, vibrator 3. The vibrator (vb) mutation is a hypomorphic allele of the phosphatidylinositol transfer protein α (PITPα) gene (pitpn) caused by the insertion of an endogenous retrovirus (intracisternal A particle, or IAP) into the fourth intron of the gene, resulting in 5 to 10-fold loss of PITPα expression. Homozygous vibrator mice show severe action tremor, progressive degeneration of interneurons in the brain stem and spinal cord, and uniform juvenile lethality. However, vibrator mice carrying Mvb1 alleles from the wild-derived CAST/Ei inbred strain show reduced tremor severity and survive to adulthood. In principle, this could be due to a change in physiological requirement for PITPα function or to a change in the steady-state expression level of PITPα derived from the mutant allele. RESULTS Mvb1 is a dosage-sensitive modifier of vibrator RNA accumulationMvb1 modifies the severity of vibrator tremor and the associated juvenile lethality 3 . To examine this effect in more detail, we monitored the longevity of vb mutant mice congenic on a C57BL/6J (B6) strain background with zero, one or two CAST/Ei alleles of Mvb1 ( Figure 1a). Consistent with our behavioral observations, the longevity data indicate a semi-dominant mode of action and high penetrance.To extend these observations to the cellular level, we examined histology of vibrator animals homozygous for either the B6 or CAST allele of Mvb1 (Figure 1b To ask whether Mvb1 acts by altering RNA levels from the mutant...

show abstract

Section: Transgenic Mouse Productioncontrasting

confidence: 64%

“…Mvb1 modifies the severity of vibrator tremor and the associated juvenile lethality 3 . To examine this effect in more detail, we monitored the longevity of vb mutant mice congenic on a C57BL/6J (B6) strain background with zero, one or two CAST/Ei alleles of Mvb1 ( Figure 1a).…”

Section: Mvb1 Is a Dosage-sensitive Modifier Of Vibrator Rna Accumulamentioning

confidence: 99%

A natural allele of Nxf1 suppresses retrovirus insertional mutations

et al. 2003

Self Cite

View full text Add to dashboard Cite

show abstract

“…The vibrator mutation caused an early-onset progressive action tremor, degeneration of brain stem and spinal cord neurons, and juvenile death. PI-TP mRNA and protein level were decreased five times in vibrator mutation (Hamilton et al, 1997). On the other hand, the increase of PI-TP level may prevent neurodegeneration.…”

Section: Discussionmentioning

confidence: 88%

“…Free radicals may also disturb phosphoinositides metabolism, transport, and signaling. It was shown previously by Hamilton et al (1997) that the vibrator mutation caused neurodegeneration-induced significant reduction of PI-TP mRNA and protein level. Till now little is known about the PI-TPs in brain aging and Parkinson disease.…”

Section: Introductionmentioning

confidence: 85%

Phosphatidylinositol Transfer Protein Expression Altered by Aging and Parkinson Disease

Chalimoniuk

Snoek²,

Adamczyk

et al. 2006

Cell Mol Neurobiol

View full text Add to dashboard Cite

SUMMARY1. Phosphatidylinositol transfer proteins (PI-TP) are responsible for the transport of phosphatidylinositol (PI) and other phospholipids from endoplasmic reticulum to the other membranes and indirectly for lipid mediated signaling. Till now little is known about PITPs in brain aging and neurodegeneration. The aim of this study was to investigate expression of PI-TP in the brain during aging and in animal's model of Parkinson disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Moreover, in vitro, effect of 1-methyl-4-phenyl-pyridine cation (MPP + ) on PI-TP, tyrosine hydroxylase (TH) protein level, and viability of cells was investigated.2. Wistar rats 4, 24, and 36 months old and C57/BL mice and rat pheochromocytoma (PC12) cell line were used for the studies. Mice C57/BL received three injections of MPTP in saline at 2 h intervals in a total dose of 40 mg/kg and then after 3, 7, and 14 days they were used for the investigation. PC12 cells were treated with increasing concentration (50-300 µM) of MPP + for 24 h at 37 • C. The level of PI-TP α and β and TH were determined using Western Blot analysis.3. Our data indicated that PI-TP α and β level decreased in brain of 36 months old rat by 20% comparing to the control value (4 months old). In animal's model of PD, PI-TP α and β level was significantly lower by 85, 69, 64% in striatum at 3, 7, and 14 days after MPTP injection, respectively, compared to the control value. MPP + decreased PI-TP α and β , TH expression, and viability of PC12 cells in a dose-dependent manner. H 2 O 2 , menadione, and NO donor significantly decreased the PI-TP level and viability of PC12 cells.4. Our results indicate the lower protein expression of PI-TP α and β in aged brain and in PD and suggest that oxidative stress may be responsible for the alteration of PI-TP.

show abstract

“…On the other hand, PI-TPb gene ablation failed to give viable ES cells (Alb et al, 2002). Very interestingly, a mutation in intron 4 of the PI-TPa gene was identified in the vibrator mouse (Hamilton et al, 1997). In these mice when homozygous in the vibrator (vb) allele brain PI-TPa levels were five-fold reduced which was accompanied by progressive action tremor, degeneration of neurons in brain and spinal cord and early juvenile death.…”

Section: Introductionmentioning

confidence: 99%