Gene Mutation Linked to One Family's Hereditary Form of Afib

I stumbled upon this interesting article today:

[www.sciencedaily.com]

It talks about a Mayo study that was done eight years ago (2008) where they discovered a gene mutation that may explain how afib is passed on in a family.

Has there been any updated studies or research on this topic? It would be interesting to know if any progress has been made on this topic in the past eight years.

Travis

This gene mutation finding/association was also reported in the discussion at the time about cardiac fibrosis formation as causative for arrhythmia... plus the magnesium deficiency factor is obviously also a contributor.

Jackie


A missense mutation in the Kv1.1 voltage-gated potassium channel–encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia
J. Clin. Invest. 119(4): 936-942 (2009).
Bob Glaudemans1, Jenny van der Wijst1, Rosana H. Scola2, Paulo J. Lorenzoni2, Angelien Heister3, AnneMiete W. van der Kemp1, Nine V. Knoers3, Joost G. Hoenderop1 and René J. Bindels1


Primary hypomagnesemia is a heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg2+) wasting, resulting in tetany, cardiac arrhythmias, and seizures. The kidney plays an essential role in maintaining blood Mg2+ levels, with a prominent function for the Mg2+-transporting channel transient receptor potential cation channel, subfamily M, member 6 (TRPM6) in the distal convoluted tubule (DCT). In the DCT, Mg2+ reabsorption is an active transport process primarily driven by the negative potential across the luminal membrane.

Here, we studied a family with isolated autosomal dominant hypomagnesemia and used a positional cloning approach to identify an N255D mutation in KCNA1, a gene encoding the voltage-gated potassium (K+) channel Kv1.1. Kv1.1 was found to be expressed in the kidney, where it colocalized with TRPM6 along the luminal membrane of the DCT. Upon overexpression in a human kidney cell line, patch clamp analysis revealed that the KCNA1 N255D mutation resulted in a nonfunctional channel, with a dominant negative effect on wild-type Kv1.1 channel function. These data suggest that Kv1.1 is a renal K+ channel that establishes a favorable luminal membrane potential in DCT cells to control TRPM6-mediated Mg2+ reabsorption.

See the related Commentary beginning on page 763.

Introduction
Occurrence of hypomagnesemia (serum Mg2+ levels below 0.70 mmol/l) in the general population has been estimated to be around 2%, while hospitalized patients are more prone to develop hypomagnesemia (12%) (1). Recent studies of intensive care patients have even estimated frequencies as high as 60% (2). The blood Mg2+ concentration depends on the renal Mg2+ excretion in response to altered uptake by the intestine. Hence, the kidney is essential for the maintenance of the Mg2+ balance (3). The majority of filtered Mg2+ is reabsorbed along the proximal tubule and the thick ascending limb of Henle’s loop via a passive paracellular pathway (4). However, fine-tuning of Mg2+ excretion occurs in the distal convoluted tubule (DCT) in an active transcellular fashion initiated by the Mg2+-permeable transient receptor potential cation channel, subfamily M, member 6 (TRPM6) (5, 6). Since the extra- and intracellular Mg2+ concentrations are both in the millimolar range, it has been hypothesized that the membrane potential across the luminal membrane acts as the primary driving force for Mg2+ entry via TRPM6 (6, 7). Previously, genetic studies in families with hereditary renal Mg2+ wasting syndromes revealed several new genes involved in Mg2+ homeostasis, including tight junction proteins claudin 16 and 19 (8, 9), the thiazide-sensitive sodium chloride cotransporter (NCC) (10), the γ-subunit of the Na+/K+-ATPase (FXYD2) (11), TRPM6 (12, 13), and the recently discovered magnesiotropic hormone EGF (14). Despite these discoveries, our knowledge of renal Mg2+ handling remains far from complete.

In this study, we screened a Brazilian family with isolated autosomal dominant hypomagnesemia and identified a missense mutation in KCNA1, resulting in nonfunctionality of the encoded voltage-gated potassium channel Kv1.1.

Results
A heterozygous KCNA1 A763G mutation is causative for hypomagnesemia. [truncated]

Continue: [www.jci.org]
Published in Volume 119, Issue 4 (April 1,2009)

1Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
2Neuromuscular Disorders Division, Clinical Hospital, Parana Federal University, Curitiba, Parana, Brazil.
3Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Address correspondence to: René J. Bindels, 286 Physiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-24-3614211; Fax: 31-24-3616413; E-mail: r.bindels@ncmls.ru.nl.
J. Clin. Invest. 119(4): 936-942 (2009). doi:10.1172/JCI36948.
Copyright © 2009, American Society for Clinical Investigation
First published March 23, 2009
Received for publication July 28, 2008, and accepted in revised form January 7, 2009.