5 HERG SCN5A Long QT Syndrome by Genetic

7/29/2019 5 HERG SCN5A Long QT Syndrome by Genetic

1/12

1. TOXIN 3. PHYSIOLOGY

2. ANIMAL

PHENOTYPE

DISCOVERY OF ION CHANNELS

5. HUMAN DISEASE4. REQUIRES AN ION

(ABNORMAL EKG)TO LIVE


2/12

IDENTIFICATION OF ION CHANNELS BY INHERITED DISEASE

positional cloningan

candidate gene approach

(Long QT syndrome)

Identification of many

disease related genes


3/12


4/12


5/12

Search for a disease gene begins with linkage analysis. In this approach, the aimis to find out the rough location of the gene relative to another DNA sequence

,

rnc pe o n age anays s: a erna ue an

maternal (red) chromosomes aligned in a germcell, a cell that gives rise to eggs or sperm. Thecapital letters represent the paternal alleles and

e ower case e ers represen e ma ernaalleles for three genes: ABC. The middle panelshows recombination, which involves crossing

over of DNA strands between the pairedc romosomes. e ma erna an pa erna a eesare mixed (recombined) and these mixedchromosomes are passed to the sperms or eggs.If A is the disease gene and B and C are genetic

,more frequently between A and C than it isbetween A and B. This allows the disease geneto be mapped relative to the markers B and C.


6/12


7/12

IDENTIFICATION OF HUMAN ION CHANNEL RELATED DISEASES

LONG-QT syndromeKvLQT1 K channel

HERG K channelSCN5A Na channel


8/12

1.4 Determining Distance Between Loci

Linkage between two genes results in fewer recombination events

- . ,linked because there are no recombinants. The proportion of gametesof each type (recombinant and non-recombinant) can be used to

,recombinants there are, the farther apart the loci are.


9/12

In linkage analysis, genes are mapped relative to one another by the likelihood ofrecombination between the mutant gene (HERG) to known regions of thechromosome with highly polymorphic alleles (microsatellites). If there is linkage

,rate will be very low.

K channels

marker

markerK channels

marker

Above is the pedigree structure and genotypic analysis of one family withinherited LQT syndrome. Disease carrying individuals are closed squares andcircles. Males are squares, females circles. Haplotypes (linked gene loci) for

, ,under each individuals. Haplotypes cosegregating with the disease phenotype

are indicated by a box. Haplotype analyses indicate that the LQT phenotype inthese kindreds is linked to markers on chromosome 7q35-36.


10/12

Below is a pedigree structure of one family and the results of PCR amplificationusing primer pair 3, 9 and the effect of the mutation on the predicted structure of theHERG protein. There two PCR products associated with the diseased individualindicating that one allele carries the deletion of HERG leading to the Long QTsyndrome


11/12


12/12

Documents

5 HERG SCN5A Long QT Syndrome by Genetic