Group 1: pathophysiology of ion channels (S. Bendahhou)

image groupe SBIon channel disorders are a diverse array of human disorders caused by mutations in ion channel genes. Channel dysfunction alters the electrical excitability of the cell and thereby increases susceptibility to transient symptomatic attacks including, periodic paralysis, myotonia, myasthenia, seizures, headache, dyskinesia, or episodic ataxia. Although these disorders are rare, they stand out as exemplary cases for which disease pathogenesis can be traced from a point mutation to altered protein function, to altered cellular activity, and to clinical phenotype.The study of these disorders has provided insights on channel structure-function relationships, the physiological roles of ion channels, and rational approaches toward therapeutic intervention for many disorders of cellular excitability.

The main topics are:

Axis 1: Role of the potassium channels in non-excitable tissues

Physiological importance of the Kir channel is highlighted by the fact that genetically-inherited defects in Kir channels are responsible for a number of human diseases that originate often from missense mutations that alter the gating mechanisms of the channel and/or its response to cellular effectors. Among these diseases, Andersen’s syndrome is a multifaceted disorder whose patients exhibit a complex clinical pattern that includes periodic paralyses, cardiac arrhythmia, and bone features. Most the most disease-causing mutations have been identified in the KCNJ2 gene that encodes the inwardly rectifying potassium Kir2.1. Kcnj2 knockout mice have been made but could not allow thorough investigations. Human induced pluripotent stem (iPS) cells could be a good alternative to these animal models in order to investigate the role of the potassium channels in excitable and non-excitable tissues.

Axis 2: Molecular determinants of naturally-occurring mutations in ion channels in excitable tissues (periodic paralysis, myotonia, paramyotonia congenita, congenital myasthenic syndrome, Andersen’s syndrome)

Inherited pathologies of skeletal muscle were the first to associate an ion channel to a disorder, including periodic paralyses, and different forms of myotonia. Na+, Ca2+, Cl-, and later on K+ channels have been clearly associated with these diseases. Manifestations in these patients and associated mutations could easily be understood through a dysregulation of the electrical excitability of skeletal muscle. We are interested in the molecular and physiological mechanisms, going from the identification of disorder-associated mutations, to understanding the physiological mechanism underlying the disease. We use mammalian expressing systems, electrophysiological, biochemical, and immunohistochemical approaches to unravel the functional consequences of these mutations.Skeletal muscles have complex structures working in concert to provide the appropriate response to nerve impulse and metabolic processes. We are interested in understanding the role of ion channels in the muscle excitability. We use muscle biopsies from patients with muscle dysfunction and animal models to study the functional properties of ion channels in human myotubes and mouse models.

Axis 3: Spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder. SMA is the most common genetic disease resulting in death in infancy (1:6000 to 1:10000 births). This pathology is primarily characterized by loss of spinal cord motor neurons that results in muscle weakness and atrophy. Clinically heterogeneous, SMA has been classified into 4 main subtypes, based on age of onset, severity of motor impairment and life span. The alpha motor neuron remains the primary site of pathology in SMA disease. However, it is not clearly established how a loss-of-function of an ubiquitously expressed protein and functionally required for all cell types has a strong impact apparently only on one cell type. Recent advances in stem cell research, especially the iPS cell technology, might aid to discover cellular and molecular process involved in this multisystemic disease, overcoming the human in vivo problems.