v 32 Ttype channel activity Robin N Stringer Bohumila JurkovicovaTarabova Sun Huang Omid Haji Ghassemi Romane Idoux Anna Liashenko Ivana A Souza Yuriy Rzhepetskyy ID: 932823
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Slide1
A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity
Robin N. Stringer,
Bohumila
Jurkovicova-Tarabova
, Sun Huang, Omid Haji-
Ghassemi
,
Romane
Idoux
,
Anna
Liashenko
, Ivana A. Souza,
Yuriy
Rzhepetskyy
,
Lubica
Lacinova
, Filip Van
Petegem
, Gerald W.
Zamponi
,
Roger
Pamphlett
and Norbert Weiss
Slide2ALS
Neurodegenerative disorder – loss of cortical, brain stem and spinal motor neurons
Causes muscle weakness, paralysis and death
Disease onset between 40 to 70 years old
Affects 1-3 people per 100,000
Inherited or familial ALS (
fALS
) occurs in 5-10% of patients
Sporadic ALS (
sALS
) in other 90-95%
Large overlap in affected genes between
fALS
and
sALS
We found two heterozygous recessive missense mutations in the gene
CACNA1H
Slide3T-type Channels
Three isoforms Ca
v
3.1,
3.2
and 3.3Low voltage activated transient calcium channelsNeuronal T-type channel key functions:Neuronal membrane oscillationsLowering threshold for action potential firing in both PNS and CNSTwo mutations P1210L and ΔI153
Δ
I153
P1210L
Slide4Loss of conductance in ΔI153 mutant in recombinant conditions
Slide5Loss of function of ΔI153 mutant in native conditions
Slide6Reduced expression of Cav3.2
Slide7Dominant-negative effect of ΔI153 mutant
Slide8Key points
P1210L mutation caused a 32% reduction in maximal conductance
Δ
I153 mutation caused complete loss of Ca
v
3.2 activityΔI153 mutation caused a 78% reduction in expression and is not present in the plasma membraneΔI153 causes a dominant-negative effect on the WT channel when expressed in trans
Slide9Thanks for listening
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