Mutation in glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias

Barry London, Michael Michalec, Haider Mehdi, Xiaodong Zhu, Laurie Kerchner, Shamarendra Sanyal, Prakash C. Viswanathan, Arnold E. Pfahnl, Lijuan L. Shang, Mohan Madhusudanan, Catherine J. Baty, Stephen Lagana, Ryan Aleong, Rebecca Gutmann, Michael J. Ackerman, Dennis M. McNamara, Raul Weiss, Samuel C. Dudley

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2260-2268
Number of pages9
JournalCirculation
Volume116
Issue number20
DOIs
StatePublished - Nov 1 2007

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Keywords

  • Arrhythmia
  • Electrophysiology
  • Genetics
  • Ion channels
  • Sodium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

London, B., Michalec, M., Mehdi, H., Zhu, X., Kerchner, L., Sanyal, S., Viswanathan, P. C., Pfahnl, A. E., Shang, L. L., Madhusudanan, M., Baty, C. J., Lagana, S., Aleong, R., Gutmann, R., Ackerman, M. J., McNamara, D. M., Weiss, R., & Dudley, S. C. (2007). Mutation in glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation, 116(20), 2260-2268. https://doi.org/10.1161/CIRCULATIONAHA.107.703330