Mutation in Glycerol-3-Phosphate Dehydrogenase 1–Like Gene ( GPD1-L ) Decreases Cardiac Na + Current and Causes Inherited Arrhythmias

• Published in: Circulation (New York, N.Y.) Vol. 116; no. 20; pp. 2260 - 2268
• Main Authors: London, Barry, Michalec, Michael, Mehdi, Haider, Zhu, Xiaodong, Kerchner, Laurie, Sanyal, Shamarendra, Viswanathan, Prakash C., Pfahnl, Arnold E., Shang, Lijuan L., Madhusudanan, Mohan, Baty, Catherine J., Lagana, Stephen, Aleong, Ryan, Gutmann, Rebecca, Ackerman, Michael J., McNamara, Dennis M., Weiss, Raul, Dudley, Samuel C.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 13.11.2007
• Subjects: Animals; Antihypertensive agents; Biological and medical sciences; Blood and lymphatic vessels; Brugada Syndrome - genetics; Brugada Syndrome - physiopathology; Cardiology. Vascular system; Cardiovascular system; Chlorocebus aethiops; Chromosomes, Human, Pair 3; COS Cells; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Family Health; Female; Glycerolphosphate Dehydrogenase - genetics; Glycerolphosphate Dehydrogenase - metabolism; Heart; Heart - physiology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humans; Italy; Kidney - cytology; Male; Medical sciences; Muscle Proteins - genetics; Muscle Proteins - metabolism; NAV1.5 Voltage-Gated Sodium Channel; Pedigree; Pharmacology. Drug treatments; Point Mutation; Sodium - metabolism; Sodium Channels - genetics; Sodium Channels - metabolism; Sugar Alcohol Dehydrogenases - genetics; Sugar Alcohol Dehydrogenases - metabolism; Ventricular Fibrillation - genetics; Ventricular Fibrillation - physiopathology; Italy; Glycerol-3-phosphate dehydrogenase; genetics; Sodium; Arrhythmia; Enzyme; Heart disease; Electrophysiology; Cardiovascular disease; Oxidoreductases; Mutation; ion channels
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.107.703330

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 ≈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. Methods and 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 ≈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.