Background-The SCN5A gene encoding the human cardiac sodium channel ␣ subunit plays a key role in cardiac electrophysiology. Mutations in SCN5A lead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease). Methods and Results-In the present study, we report the identification of a novel single SCN5A missense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406R SCN5A mutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutated SCN5A showed no detectable Na ϩ current but normal protein trafficking. Conclusions-We conclude that the same mutation in the SCN5A gene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of a SCN5A mutation. Key Words: fibrillation Ⅲ heart block Ⅲ bundle-branch block Ⅲ genetics Ⅲ arrhythmia T he SCN5A gene encoding a voltage-gated Na ϩ channel is predominantly expressed in the heart, where it plays a key role in the generation and propagation of the cardiac impulse. Autosomal-dominant mutations in the SCN5A gene are responsible for distinct rhythm and conduction disorders, including the long-QT syndrome (LQT3), 1 Brugada syndrome, 2 and isolated cardiac conduction defect (ICCD; Lenègre disease). 3,4 Distinct ECG phenotypes and risks characterize these syndromes. The LQT3 phenotype is characterized by a prolonged QT interval, potentially leading to torsade de pointes arrhythmias. At the cellular level, the pathophysiology sequence for LQT3 includes slowed inactivation of the Na ϩ current, resulting in a sustained inward current (gain of function) during the plateau of the cardiac action potential. 5 The Brugada phenotype is characterized by ST-segment elevation in the right precordial leads, often accompanied (albeit not always) by right bundle branch block but a normal QT duration. 6 As originally described, Brugada syndrome is associated with a high mortality resulting from nocturnal ventricular fibrillation. 7 The pathophysiology sequence of the Brugada syndrome remains incompletely understood, although the syndrome possibly results from a...

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The voltage-gated sodium channel Na V 1.5 is responsible for the initial upstroke of the action potential in cardiac tissue. Levels of intracellular calcium modulate inactivation gating of Na V 1.5, in part through a C-terminal EF-hand calcium binding domain. The significance of this structure is underscored by the fact that mutations within this domain are associated with specific cardiac arrhythmia syndromes. In an effort to elucidate the molecular basis for calcium regulation of channel function, we have determined the solution structure of the C-terminal EFhand domain using multidimensional heteronuclear NMR. The structure confirms the existence of the four-helix bundle common to EF-hand domain proteins. However, the location of this domain is shifted with respect to that predicted on the basis of a consensus 12-residue EF-hand calcium binding loop in the sequence. This finding is consistent with the weak calcium affinity reported for the isolated EF-hand domain; high affinity binding is observed only in a construct with an additional 60 residues C-terminal to the EF-hand domain, including the IQ motif that is central to the calcium regulatory apparatus. The binding of an IQ motif peptide to the EF-hand domain was characterized by isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. The peptide binds between helices I and IV in the EF-hand domain, similar to the binding of target peptides to other EF-hand calcium-binding proteins. These results suggest a molecular basis for the coupling of the intrinsic (EF-hand domain) and extrinsic (calmodulin) components of the calciumsensing apparatus of Na V 1.5.The cardiac voltage-gated sodium channel Na V 1.5 mediates the voltage-dependent sodium ion permeability of excitable membranes. Na V 1.5 is responsible for the initial upstroke of the action potential in the electrocardiogram. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein allows Na ϩ ions to pass in accordance with their electrochemical gradient. Upon repeated stimulation, channels convert to the third state known as the inactive state. Channels must pass from the inactive to the closed state before they can be opened again. The structure of the channel is dominated by four membrane spanning domains (DI, DII, DIII, DIV), each containing six transmembrane helices linked by intracellular loops. The loop between DIII and DIV is of particular interest here because it is involved in the fast-inactivation of the channel (1). There are also substantial N-and the C-terminal domains, both located on the cytoplasmic side of the membrane. Several diseases are linked to the dysfunction of Na V 1.5, such as long QT syndrome, Brugada syndrome, and idiopathic ventricular fibrillation (2-6), and some of these dysfunctions are due to mutations located in the C-terminal domain (7-9).Substantial evidence has accumulated showing that inactivation gating of Na V 1.5 is modulated in response to changes in the level of calcium (Ca 2ϩ ) in the ad...

Ten patients in whom cystic dystrophy developed in a heterotopic pancreas of the duodenal (nine patients) or gastric (one patient) wall are reported. All were young or middle aged white men, only two of whom were alcoholic. The symptoms were caused by intestinal or biliary stenosis, or both, secondary to the inflammation and fibrosis. Only endosonography provided strong evidence for the diagnosis in three patients. All patients underwent surgery: a pancreaticoduodenectomy was performed in eight patients. The surgical specimen showed cystic lesions of the gut wall, occurring in inflammatory and fibrous heterotopic pancreatic tissue. The pancreas proper was normal in all patients. It is suggested that cystic dystrophy is an uncommon and serious complication of heterotopic pancreas. Similar cases associated with chronic pancreatitis of the pancreas have been observed and it is suggested that this process could be responsible for some of the chronic pancreatitis encountered in young, non-alcoholic patients.