1/3. bradycardia-induced long qt syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG.long qt syndrome is a congenital disorder that presents with a defective cardiac ion channel and is either associated with prolonged action potential or, more commonly, known as an acquired form in which "torsades de pointes" type arrhythmias specifically occur after secondary causes. We report a case of a novel HERG mutation (A490T) that caused a bradycardia-associated form of long QT syndrome. A 27-year-old woman exhibited recurrent syncope due to torsades de pointes associated with a disturbance of the cardiac conduction system. By using polymerase chain reaction and single strand conformational polymorphism analyses, we identified a heterozygous single nucleotide substitution of HERG (G to A at nt 1468). This mutational change was not present in 140 Japanese control individuals. Electrophysiological assays for the A490T mutant HERG channel were conducted in the heterologous expression system with COS7 cells. The mutant channel was found to reconstitute functional channel currents, suggesting the homomeric mutant channel was functional. The mutation did not change the properties of the activation gate and inward rectification, however the current density of this mutant channel was small compared with that of wild type HERG. Taken together, this mutant may cause subtle changes in HERG channel functions (I(Kr)) in vivo. In this case, genetic background and unexpected bradycardia may have contributed to the development of long qt syndrome.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |
2/3. Pacemaker channel dysfunction in a patient with sinus node disease.The cardiac pacemaker current I(f) is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of "idiopathic" sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide-binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated I(f)-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac I(f) channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient's sinus bradycardia and the chronotropic incompetence.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |
3/3. Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms.BACKGROUND: Congenital atrial standstill has been linked to SCN5A. Incomplete penetrance observed in atrial standstill has been attributed in part to the digenic inheritance of polymorphisms in the atrial-specific gap junction connexin 40 (Cx40) in conjunction with an SCN5A mutation. OBJECTIVES: The purpose of this study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation identified in a family with atrial standstill. methods: family members of an apparently sporadic case of atrial standstill underwent genetic screening of SCN5A and atrial-specific genes including Cx40. Biophysical properties of the wild-type (WT) and mutant SCN5A channels in a heterologous expression system were studied using the whole-cell patch clamp technique. RESULTS: The novel SCN5A mutation L212P was identified in the proband (age 11 years) and his father. The father was in normal sinus rhythm. The proband had no P waves on surface ECG, and his right atrium could not be captured by pacing. The recombinant L212P Na channel showed a large hyperpolarizing shift in both the voltage dependence of activation (WT: -48.1 /- 0.9 mV; L212P: -63.5 /- 1.5 mV; P < .001) and inactivation (WT: -86.6 /- 0.9 mV; L212P: -95.6 /- 0.8 mV; P < .001) and delayed recovery from inactivation. Further screenings for genetic variations that might mitigate L212P dysfunction revealed that the proband, but not his father, carries Cx40 polymorphisms inherited from his asymptomatic mother. CONCLUSION: These results suggest that genetic defects in SCN5A most likely underlie atrial standstill. Coinheritance of Cx40 polymorphisms is a possible genetic factor that modifies the clinical manifestation of this inherited arrhythmia.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |