Four and a Half Lim Domains (FHL) Genes Reduce Conductivity of the KCNA5 Channel

Myopathies are inherited muscle disorders characterized by weakness and atrophy of voluntary skeletal muscles, sometimes including the cardiac muscle. A phenotypically distinct, X-linked myopathy with postural muscle atrophy, termed XMPMA, has been recently described and linked to mutations in the FHL1 gene. FHL1, a member of LIM-only proteins, is expressed in skeletal and cardiac muscle and suggested to play a role in sarcomere synthesis and assembly. Three splice variants (A, B and C) exist, which differ in expression pattern, binding partners and subcellular localization. A mutation found in a large XMPMA family (C224W) affects only isoforms A and B.Aim of our study is to functionally characterize mutated FHL1 isoforms and their interaction with the voltage-gated potassium channel (KCNA5 or Kv1.5), which is involved in cardiac excitability. These interactions may partly explain the cardiac involvement within the clinical spectrum of XMPMA patients.K+ currents were recorded in Xenopus leavis oocytes injected with KCNA5 mRNA with or without coexpression of FHL1AWT, FHL1AC224W or FHL1C. Upon coexpression of all three FHL1 proteins, K+ current density was differently decreased, when compared to oocytes expressing KCNA5 alone. Kinetics of the channel was not affected. These results support the role of FHL1 as a key molecular component in regulation of expression of KCNA5. Future experiments will concentrate on colocalization and molecular interaction of FHL1 and KCNA5 in mammalian in vitro systems (HL1 cells).Support by Graz Medical University Ph.D. programme and County of Styria (GZ: A3-16.R-10/2009-112).