A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5.
BACKGROUND
Mutations in genes including SCN5A encoding the α-subunit of the cardiac sodium channel (hNav1.5) cause Brugada syndrome via altered function of cardiac ion channels, but more than two-thirds of Brugada syndrome remains pathogenetically elusive. T-tubules and sarcoplasmic reticulum are essential in excitation of cardiomyocytes, and sarcolemmal membrane-associated protein (SLMAP) is a protein of unknown function localizing at T-tubules and sarcoplasmic reticulum.


RESULTS
We analyzed 190 unrelated Brugada syndrome patients for mutations in SLMAP. Two missense mutations, Val269Ile and Glu710Ala, were found in heterozygous state in 2 patients but were not found in healthy individuals. Membrane surface expression of hNav1.5 in the transfected cells was affected by the mutations, and silencing of mutant SLMAP by small interfering RNA rescued the surface expression of hNav1.5. Whole-cell patch-clamp recordings of hNav1.5-expressing cells transfected with mutant SLMAP confirmed the reduced hNav1.5 current.


CONCLUSIONS
The mutations in SLMAP may cause Brugada syndrome via modulating the intracellular trafficking of hNav1.5 channel.
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Taisuke
T
Ishikawa
Akinori
A
Sato
Cherisse A
CA
Marcou
David J
DJ
Tester
Michael J
MJ
Ackerman
Lia
L
Crotti
Peter J
PJ
Schwartz
Young Keun
YK
On
Jeong-Euy
JE
Park
Kazufumi
K
Nakamura
Masayasu
M
Hiraoka
Kiyoshi
K
Nakazawa
Harumizu
H
Sakurada
Takuro
T
Arimura
Naomasa
N
Makita
Akinori
A
Kimura
D053840:Brugada Syndrome / Q000235:genetics*; D016022:Case-Control Studies; D020868:Gene Silencing / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D014162:Transfection
D008565:Membrane Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D034741:RNA, Small Interfering; C568320:SCN5A protein, human; C109742:SLMAP protein, human