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From: Sodium Channel Mutations and Susceptibility to Heart Failure and Atrial Fibrillation
JAMA. 2005;293(4):447-454. doi:10.1001/jama.293.4.447
Figure Legend:
Phenotypic traits are variably expressed, designated by shaded quadrantswithin pedigree symbols. Genotypes for closely spaced
DNA markers are shownas numbers, representing different lengths of short tandem repeat marker allelesthat distinguish the
paternally and maternally inherited chromosomal region.Markers are located within the previously reported disease gene locus on
chromosome3p22-p25. The distance of each marker from the p-arm telomere is indicatedby Mb (megabase). The 4 central markers
(5-4-5-2) within the shaded chromosomesegment
define a©haplotype,
a group
of alleles inherited as a unit, commonto all family
Copyright
2005 American
Medical
Date
of download:
5/2/2017
members
with cardiac
disease. Recombination events
indicatethat
the
disease-causing
gene resides between markers D3S3727
Association. All rights reserved.
and D3S3559. SCN5A, located at 38.6-Mb, was investigated asa candidate gene. A point mutation in SCN5A that alters a
From: Sodium Channel Mutations and Susceptibility to Heart Failure and Atrial Fibrillation
JAMA. 2005;293(4):447-454. doi:10.1001/jama.293.4.447
Figure Legend:
A, Heteroduplex mutation scans of exons comprising the entire codingregion of SCN5A were performed by denaturing highperformanceliquid chromatography (DHPLC). Heterozygous variation in DNA sequence wasdetected in exons 6, 16, 17, 21, and 27
for the 5 family probands in Figure 1 and Figure 3. In contrast to normal exons generating single peaks on chromatographicprofiles,
exons harboring mutations had anomalous profiles characterized by2 peaks. B, To determine if detected variations were benign or
pathogenic,genomic DNA sequencing was performed.
In 4
theAmerican
exons (exons
6, 16, 21,and 27), mutations were discovered in 1
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© of
2005
Medical
Date
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the gene, 5/2/2017
resulting in aminoacid substitutions.
In
the
remaining
exon
(exon
17), insertion of 2 basesdisrupts the coding
Association. All rights reserved.
sequence (only the mutant gene is shown). C, Regions inthe cardiac sodium channel protein altered by mutations were aligned
From: Sodium Channel Mutations and Susceptibility to Heart Failure and Atrial Fibrillation
JAMA. 2005;293(4):447-454. doi:10.1001/jama.293.4.447
Figure Legend:
Haplotypes at the chromosome 3p locus where SCN5A is located are shown. Each shaded haplotype defines a
chromosomalsegment that harbors a mutant SCN5A gene. In 2 families,point mutations caused amino acid substitutions: D1595H in
DC-30 and T220Iin DC-31. In DC-26, the insertion of 2 bases in the mutant gene results ina truncated protein that terminates in a
string of 18 anomalous amino acids(fs851 [frameshift at amino acid 851]; Figure 2C). In DC-96, neither of theproband’s parents and
none of her 7 siblings had cardiac disease. Thehaplotypes
her father (dark blue) and mother (light purple)are also
Copyright © she
2005inherited
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inherited
by other 5/2/2017
siblings, yet she is the only family
member
witha
mutation
in
Association. All rights reserved.SCN5A. These findings indicate thatthe point
mutation, R814W, arose as a spontaneous, or de novo, event on eitherthe paternal or maternal chromosome. SVT indicates