A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete - PowerPoint Presentation

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Uploaded On 2022-08-02

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete - PPT Presentation

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

loss i153 channel mutant i153 loss mutant channel type caused mutation p1210l als conductance key mutations conditions expression dominant

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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

Slide2

ALS

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

Slide3

T-type Channels

Three isoforms Ca

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

I153

P1210L

Slide4

Loss of conductance in ΔI153 mutant in recombinant conditions

Slide5

Loss of function of ΔI153 mutant in native conditions

Slide6

Reduced expression of Cav3.2

Slide7

Dominant-negative effect of ΔI153 mutant

Slide8

Key points

P1210L mutation caused a 32% reduction in maximal conductance

I153 mutation caused complete loss of Ca

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

Slide9

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