Journal ArticleDOI
Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families
A. Tammaro,A. Di Martino,A. Bracco,S. Cozzolino,Gennaro Savoia,Barbara Andria,Alessandro Cannavo,M Spagnuolo,Giulio Piluso,S. Aurino,Vincenzo Nigro +10 more
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TLDR
Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families in 75malignant hyperThermia families are found.Abstract:
Tammaro A, Di Martino A, Bracco A, Cozzolino S, Savoia G, Andria B, Cannavo A, Spagnuolo M, Piluso G, Aurino S, Nigro V. Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families.
Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder of skeletal muscle characterized by disturbance of intracellular calcium homeostasis in the sarcoplasmic reticulum. Mutations of the ryanodine receptor 1 (RYR1) gene account for most cases, with some studies claiming up to 86% of mutations in this locus. However, RYR1 gene is large and variants are common even in the normal population. We examined 54 families with MH susceptibility and 21 diagnosed with equivocal MH. Thirty-five were selected for an anesthetic reaction, whereas the remainder for hyperCKemia. In these, we studied all 106 exons of the RYR1 gene. When no mutation was found, we also screened: sodium channel voltage-gated, type IV alpha subunit (SCN4A), calcium channel voltage-dependent, L type, alpha 1S subunit (CACNA1S), and L-type voltage-gated calcium channel alpha 2/delta-subunit (CACNL2A). Twenty-nine different RYR1 mutations were discovered in 40 families. Three other MH genes were tested in negative cases. Fourteen RYR1 amino acid changes were novel, of which 12 were located outside the mutational ‘hot spots'. In two families, the known mutation p.R3903Q was also observed in malignant hyperthermia-nonsusceptible (MHN) individuals. Unexpectedly, four changes were also found in the same family and two in another. Our study confirms that MH is genetically heterogeneous and that a consistent number of cases are not due to RYR1 mutations. The discordance between in vitro contracture test status and the presence of a proven causative RYR1 mutation suggests that the penetrance may vary due to as yet unknown factors.read more
Citations
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Journal ArticleDOI
Clinical and Genetic Findings in a Large Cohort of Patients with Ryanodine Receptor 1 Gene-Associated Myopathies
Andrea Klein,S. Lillis,Iulia Munteanu,Mariacristina Scoto,Haiyan Zhou,Ros Quinlivan,Volker Straub,Adnan Y. Manzur,Helen Roper,Pierre-Yves Jeannet,Wojtek Rakowicz,David P.H. Jones,Uffe Birk Jensen,Elizabeth Wraige,Natalie Trump,Ulrike Schara,Hanns Lochmüller,Anna Sarkozy,Helen Kingston,Fiona Norwood,Maxwell S. Damian,Janbernd Kirschner,Cheryl Longman,Mark Roberts,Michaela Auer-Grumbach,Imelda Hughes,Kate Bushby,Caroline Sewry,Stephanie Robb,Stephen Abbs,Heinz Jungbluth,Heinz Jungbluth,Francesco Muntoni +32 more
TL;DR: A large number of novel RYR1 mutations are reported and indicates that recessive variants are at least as frequent as the dominant ones, and that patients with recessive inheritance had earlier onset, more weakness, and functional limitations.
Journal ArticleDOI
Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept.
TL;DR: The various RYR1-related disorders and phenotypes, such as myopathies, exertional rhabdomyolysis, and bleeding disorders, are reviewed, and the connection between these disorders and malignant hyperthermia is examined.
Journal ArticleDOI
RYR1-related myopathies: a wide spectrum of phenotypes throughout life.
M. Snoeck,B.G.M. van Engelen,Benno Küsters,Benno Küsters,Martin Lammens,Martin Lammens,Rowdy Meijer,Joery P. Molenaar,Joost Raaphorst,Corien C. Verschuuren-Bemelmans,Chiara S. M. Straathof,L.T.L. Sie,I.F.M. de Coo,W. L. van der Pol,M. de Visser,Hans Scheffer,Susan Treves,Heinz Jungbluth,Heinz Jungbluth,Nicol C. Voermans,E. Kamsteeg +20 more
TL;DR: The aim of the present study was to investigate the full spectrum of RYR1‐related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia.
Journal ArticleDOI
Crystal structures of wild type and disease mutant forms of the ryanodine receptor SPRY2 domain.
Kelvin Lau,Filip Van Petegem +1 more
TL;DR: The SPRY2 domain in the skeletal muscle isoform (RyR1) has been proposed as a direct link with L-type calcium channels (CaV1.1), allowing for direct mechanical coupling between plasma membrane depolarization and Ca(2+) release.
Journal ArticleDOI
Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness
Dorota Fiszer,Marie-Anne Shaw,Nickla A. Fisher,Ian M. Carr,Pawan K. Gupta,Elizabeth J. Watkins,Daniel Roiz de Sa,Jerry H. Kim,Philip M. Hopkins +8 more
TL;DR: Targeted next-generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and EHI.
References
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Journal ArticleDOI
Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia
David H. MacLennan,Catherine Duff,Francesco Zorzato,Junichi Fujii,Michael A. Phillips,Robert G. Korneluk,Wanda Frodis,Beverley A. Britt,Ronald G. Worton +8 more
TL;DR: Co-segregation of MH with RYRmarkers, resulting in a lod score of 4.20 at a linkage distance of zero centimorgans, indicates that MH is likely to be caused by mutations in the RYR gene.
Journal ArticleDOI
Mutations in RYR1 in malignant hyperthermia and central core disease.
TL;DR: The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation–contraction coupling and skeletal muscle calcium homeostasis.
Journal ArticleDOI
Malignant-Hyperthermia Susceptibility Is Associated with a Mutation of the a1-Subunit of the Human Dihydropyridine-Sensitive L-Type Voltage-Dependent Calcium-Channel Receptor in Skeletal Muscle
TL;DR: It is shown that the CACNL1A3 gene encoding the alpha 1-subunit of the human skeletal muscle dihydropyridine-sensitive L-type voltage-dependent calcium channel (VDCC) represents a new MHS locus and is responsible for the disease in a large French family, the first direct evidence that the skeletal muscle VDCC is involved in MHS.
Journal ArticleDOI
Localization of the malignant hyperthermia susceptibility locus to human chromosome 19q12-13.2.
Tommie V. McCarthy,J. M. S. Healy,James J. A. Heffron,M. Lehane,T. Deufel,Frank Lehmann-Horn,Martin Farrall,Martin Farrall,Keith J. Johnson +8 more
TL;DR: Linkage between MHS and DNA markers from the GPI region of human chromosome 19 with a maximum log likelihood ratio (lod score) of 5.65 indicates that human and porcine MH are most probably due to mutations in homologous genes, and provides a potentially accurate and noninvasive method of diagnosis for MHS.
Journal ArticleDOI
A mutation in the human ryanodine receptor gene associated with central core disease.
Yilin Zhang,Chen Hs,Vijay K. Khanna,De Leon S,Michael S. Phillips,Schappert K,Beverley A. Britt,Browell Ak,David H. MacLennan +8 more
TL;DR: A causal relationship between malignant hyperthermia (MH) and central core disease (CCD) has been found in this paper, with a lod score of 48 at a recombinant fraction of 00 in 16 informative meioses in a 130 member family.
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Clinical and Genetic Findings in a Large Cohort of Patients with Ryanodine Receptor 1 Gene-Associated Myopathies
Andrea Klein,S. Lillis,Iulia Munteanu,Mariacristina Scoto,Haiyan Zhou,Ros Quinlivan,Volker Straub,Adnan Y. Manzur,Helen Roper,Pierre-Yves Jeannet,Wojtek Rakowicz,David P.H. Jones,Uffe Birk Jensen,Elizabeth Wraige,Natalie Trump,Ulrike Schara,Hanns Lochmüller,Anna Sarkozy,Helen Kingston,Fiona Norwood,Maxwell S. Damian,Janbernd Kirschner,Cheryl Longman,Mark Roberts,Michaela Auer-Grumbach,Imelda Hughes,Kate Bushby,Caroline Sewry,Stephanie Robb,Stephen Abbs,Heinz Jungbluth,Heinz Jungbluth,Francesco Muntoni +32 more