LQT4: GENE ANKB

Link to: LQT4 Locus table - ANK2 mutations

External links: OMIM 600919 - Gene - cDNA (splice variants) - Protein

The only study published reporting a chromosome 4 locus for long QT syndrome (LQTS) was published in 1995 by Schott et al. In this study a single 4 generations family is described, where genome wide linkage analysis allowed the demonstration of significant LOD score in a 18 cM segment on long arm of chromosome 4 (cytogenetic bands 25-27). Fifty-six individuals (21 affected) were studied. Of note, the clinical phenotype of affected individuals differed from the classical clinical presentation commonly described for LQTS. Severe sinus bradycardia and paroxysmal atrial fibrillation constituted relatively frequent findings among these patients. Moreover, the authors describe a peculiar and atypical (Moss et al 1995) ECG pattern with very pronounced U waves clearly distinct from T wave end.

So far no other LQTS families with a significant linkage to this locus have been described and the gene involved is still unknown. Therefore, LQT4 appears to be a rare form of LQTS.

In February 2003 Mohler et al. reported the first LQT4 mutation in the same family in which the LQT4 locus was initially identified. They showed a single amino acid substitution E1425G in the ankyrin-B gene fully co-segregating with the phenotype. ANKB is a member of a family of versatile membrane adapters, involved in the targeting of several proteins and ion channel to the plasmalemma. The authors also showed that "mice heterozygous for a null mutation in ankyrin-B are haploinsufficient and display arrhythmia similar to humans. Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level. Ankyrin-B mutation also leads to altered Ca2+ signaling".

LQT4 appears to be a rare form of Long QT syndrome which manifest with an atypical phenotype also including atrial arrhythmias and sinus node dysfunction, not usually observed in the "typical" LQTS patients. Additional phenotypes have been linked to ANK2 mutations

Mohler et al have reported additional ANKB mutations in June 2004. Eight unrelated probands were shown to harbor loss of function ANKB mutations. These patients presented a clinical phenotype distinguished from that typical of the long QT syndrome and it was characterized by sinus bradycardia, sinus arrhythmias, idiopathic ventricular fibrillation and ventricular arrhythmias. The mutations were localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B to ankyrin-G in cardiomyocytes. These authors showed that all mutants abolish ability of ankyrin-B to restore abnormal Ca2+ dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase and InsP(3)R. These findings further support the pathophysiological role of cardiac ANKB in the pathogenesis of cardiac arrhythmias.