The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: Positional complementation cloning and extragenic suppression

被引:159
作者
Hamilton, BA
Smith, DJ
Mueller, KL
Kerrebrock, AW
Bronson, RT
vanBerkel, V
Daly, MJ
Kruglyak, L
Reeve, MP
Nemhauser, JL
Hawkins, TL
Rubin, EM
Lander, ES
机构
[1] WHITEHEAD INST BIOMED RES,CAMBRIDGE CTR 9,CAMBRIDGE,MA 02142
[2] UNIV CALIF BERKELEY,CTR HUMAN GENOME,BERKELEY,CA 94720
[3] TUFTS UNIV,SCH MED,BOSTON,MA 02111
[4] TUFTS UNIV,SCH VET MED,BOSTON,MA 02111
[5] JACKSON LAB,BAR HARBOR,ME 04609
[6] MIT,DEPT BIOL,CAMBRIDGE,MA 02139
关键词
D O I
10.1016/S0896-6273(00)80312-8
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:711 / 722
页数:12
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