Muscle biopsy and cell cultures: potential diagnostic tools in hereditary skeletal muscle channelopathies

Abstract

Hereditary muscle channelopathies are caused by dominant mutations in the genes encoding for subunits of muscle voltage- gated ion channels. Point mutations on the human skeletal muscle Na+ channel (Nav1.4) give rise to hyperkalemic periodic paralysis, potassium aggravated myotonia, paramyotonia congenita and hypokalemic periodic paralysis type 2. Point mutations on the human skeletal muscle Ca2+ channel give rise to hypokalemic periodic paralysis and malignant hyperthermia. Point mutations in the human skeletal chloride channel ClC-1 give rise to myotonia congenita. Point mutations in the inwardly rectifying K+ channel Kir2.1 give rise to a syndrome characterized by periodic paralysis, severe cardiac arrhythmias and skeletal alterations (Andersen’s syndrome). Involvement of the same ion channel can thus give rise to different phenotypes. In addition, the same mutation can lead to different phenotypes or similar phenotypes can be caused by different mutations on the same or on different channel subtypes. Bearing in mind, the complexity of this field, the growing number of potential channelopathies (such as the myotonic dystrophies), and the time and cost of the genetic procedures, before a biomolecular approach is addressed, it is mandatory to apply strict diagnostic protocols to screen the patients. In this study we propose a protocol to be applied in the diagnosis of the hereditary muscle channelopathies and we demonstrate that muscle biopsy studies and muscle cell cultures may significantly contribute towards the correct diagnosis of the channel involved. DNAbased diagnosis is now a reality for many of the channelopathies. This has obvious genetic counselling, prognostic and therapeutic implications

Mutations in DPAGT1 Cause a Limb-Girdle Congenital Myasthenic Syndrome with Tubular Aggregates

“…Tubular aggregates are rare and have been previously observed in certain cases with myopathies, myotonia, or myotonic dystrophy, in some cases with channelopathies, and in most individuals with CMS caused by mutations in GFPT1. 3,39,40 Both DPAGT1 and GFPT1 are required for protein glycosylation, which in turn is essential for correct protein folding and targeting. 41 It might be that in the individuals with compromised function of DPAGT1 and GFPT1, certain cellular transmembrane and secreted proteins are not appropriately glycosylated; this will lead to their misfolding and aggregation in the sarcoplasmic reticulum and the subsequent formation of tubular aggregates.…”

Fiber-Type Shifting in Sarcopenia of Old Age: Proteomic Profiling of the Contractile Apparatus of Skeletal Muscles

“…Traditional IHC is commonly used as a technique that assists pathologists in making careful decisions regarding differential diagnosis, disease subtyping and designing personalized treatment plans [144], and plays a key role in the evaluation of skeletal muscle biopsy specimens [145]. IHC and IFM techniques are also used for verification studies in proteomics [133,140].…”