King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene
ABSTRACT King-Denborough syndrome (KDS), first described in 1973, is a rare condition characterised by the triad of dysmorphic features, myopathy, and malignant hyperthermia susceptibility (MHS). Autosomal dominant inheritance with variable expressivity has been reported in several cases. Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been implicated in a wide range of myopathies such as central core disease (CCD), the malignant hyperthermia (MH) susceptibility trait and one isolated patient with KDS. Here we report clinical, pathologic and genetic features of four unrelated patients with KDS. Patients had a relatively uniform clinical presentation but muscle biopsy findings were highly variable. Heterozygous missense mutations in RYR1 were uncovered in three out of four families, of which one mutation was novel and two have previously been reported in MH. Further RyR1 protein expression studies performed in two families showed marked reduction of the RyR1 protein, indicating the presence of allelic RYR1 mutations not detectable on routine sequencing and potentially explaining marked intrafamilial variability. Our findings support the hypothesis that RYR1 mutations are associated with King-Denborough syndrome but that further genetic heterogeneity is likely.
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ABSTRACT: Genetic screens for behavioral and physiological defects in Drosophila melanogaster, helped identify several components of calcium signaling of which some, like the Trps, were novel. For genes initially identified in vertebrates, reverse genetic methods have allowed functional studies at the cellular and systemic levels. The aim of this review is to explain how various genetic methods available in Drosophila have been used to place different arms of Ca2+ signaling in the context of organismal development, physiology and behavior. MAJOR CONCLUSION: Mutants generated in genes encoding a range of Ca2+ transport systems, binding proteins and enzymes affect multiple aspects of neuronal and muscle physiology. Some also affect the maintenance of ionic balance and excretion from malpighian tubules and innate immune responses in macrophages. Aspects of neuronal physiology affected include synaptic growth and plasticity, sensory transduction, flight circuit development and function. Genetic interaction screens have shown that mechanisms of maintaining Ca2+ homeostasis in Drosophila are cell specific and require a synergistic interplay between different intracellular and plasma membrane Ca2+ signaling molecules. Insights gained through genetic studies of conserved Ca2+ signaling pathways have helped understand multiple aspects of fly physiology. The similarities between mutant phenotypes of Ca2+ signaling genes in Drosophila with certain human disease conditions, especially where homologous genes are causative factors, are likely to aid in the discovery of underlying disease mechanisms and help develop novel therapeutic strategies. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signalling.Biochimica et Biophysica Acta 11/2011; 1820(8):1269-82. DOI:10.1016/j.bbagen.2011.11.002 · 4.66 Impact Factor
Article: Core Myopathies[Show abstract] [Hide abstract]
ABSTRACT: The core myopathies, Central Core Disease and Multiminicore Disease, are heterogeneous congenital myopathies with the common defining histopathological feature of focally reduced oxidative enzyme activity (central cores, multiminicores). Mutations in the gene encoding for the skeletal muscle ryanodine (RyR1) receptor are the most common cause. Mutations in the selenoprotein N (SEPN1) gene cause a less common variant. Pathogenic mechanisms underlying dominant RYR1 mutations have been extensively characterized, whereas those associated with recessive RYR1 and SEPN1 mutations are emerging. Identifying a specific genetic defect from the histopathological diagnosis of a core myopathy is complex and ought to be informed by a combined appraisal of histopathological, clinical, and, increasingly, muscle magnetic resonance imaging data. The present review aims at giving an overview of the main genetic and clinicopathological findings, with a major emphasis on features likely to inform the diagnostic process, as well as current treatments and perspectives for future research.Seminars in pediatric neurology 12/2011; 18(4):239-49. DOI:10.1016/j.spen.2011.10.005 · 1.88 Impact Factor
Article: Congenital Fiber-Type Disproportion[Show abstract] [Hide abstract]
ABSTRACT: Congenital fiber-type disproportion is a form of congenital myopathy that may be best viewed as a syndrome rather than as a formal diagnosis. The central histologic abnormality is that type 1 fibers are consistently smaller than type 2 fibers by at least 35%-40%. Care is needed in diagnosing patients, as this histologic abnormality can occur in other congenital myopathies and in other neuromuscular disorders. Many of the genetic causes have been identified. Careful surveillance of respiratory function is required in all patients until the specific genetic cause is known and advice can be individualized.Seminars in pediatric neurology 12/2011; 18(4):264-71. DOI:10.1016/j.spen.2011.10.008 · 1.88 Impact Factor