Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias.
BACKGROUND
Brugada syndrome is a rare, autosomal-dominant, male-predominant form of idiopathic ventricular fibrillation characterized by a right bundle-branch block and ST elevation in the right precordial leads of the surface ECG. Mutations in the cardiac Na+ channel SCN5A on chromosome 3p21 cause approximately 20% of the cases of Brugada syndrome; most mutations decrease inward Na+ current, some by preventing trafficking of the channels to the surface membrane. We previously used positional cloning to identify a new locus on chromosome 3p24 in a large family with Brugada syndrome and excluded SCN5A as a candidate gene.


RESULTS
We used direct sequencing to identify a mutation (A280V) in a conserved amino acid of the glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) gene. The mutation was present in all affected individuals and absent in >500 control subjects. GPD1-L RNA and protein are abundant in the heart. Compared with wild-type GPD1-L, coexpression of A280V GPD1-L with SCN5A in HEK cells reduced inward Na+ currents by approximately 50% (P<0.005). Wild-type GPD1-L localized near the cell surface to a greater extent than A280V GPD1-L. Coexpression of A280V GPD1-L with SCN5A reduced SCN5A cell surface expression by 31+/-5% (P=0.01).


CONCLUSIONS
GPD1-L is a novel gene that may affect trafficking of the cardiac Na+ channel to the cell surface. A GPD1-L mutation decreases SCN5A surface membrane expression, reduces inward Na+ current, and causes Brugada syndrome.
London
Barry
B
Cardiovascular Institute, University of Pittsburgh Medical Center, Scaife S-572, 200 Lothrop St, Pittsburgh, PA 15213-2582, USA. londonb@upmc.edu
Michalec
Michael
M
Mehdi
Haider
H
Zhu
Xiaodong
X
Kerchner
Laurie
L
Sanyal
Shamarendra
S
Viswanathan
Prakash C
PC
Pfahnl
Arnold E
AE
Shang
Lijuan L
LL
Madhusudanan
Mohan
M
Baty
Catherine J
CJ
Lagana
Stephen
S
Aleong
Ryan
R
Gutmann
Rebecca
R
Ackerman
Michael J
MJ
McNamara
Dennis M
DM
Weiss
Raul
R
Dudley
Samuel C
SC
D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D002893:Chromosomes, Human, Pair 3; D005192:Family Health; D005260:Female; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006801:Humans; D007558:Italy; D007668:Kidney / Q000166:cytology; D008297:Male; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D017354:Point Mutation; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013401:Sugar Alcohol Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000235:genetics / Q000503:physiopathology
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D012964:Sodium; C525035:GPD1L protein, human; D005993:Glycerolphosphate Dehydrogenase; D013401:Sugar Alcohol Dehydrogenases