The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility
ABSTRACT It has been suggested that exertional rhabdomyolysis (ER) and malignant hyperthermia (MH) are related syndromes. We hypothesize that patients with unexplained ER harbor mutations in the ryanodine receptor gene type 1 (RYR1), a primary gene implicated in MH, and therefore ER patients are at increased risk for MH. Although there are reported cases of MH in individuals of African descent, there are no data available on molecular characterization of these patients. We analyzed RYR1 in six, unrelated African American men with unexplained ER, who were subsequently diagnosed as MH susceptible (MHS) by the Caffeine Halothane Contracture Test. Three novel and two variants, previously reported in Caucasian MHS subjects, were found in five studied patients. The novel variants were highly conserved amino acids and were absent among 230 control subjects of various ethnic backgrounds. These results emphasize the importance of performing muscle contracture testing and RYR1 mutation screening in patients with unexplained ER. The MHS-associated variant Ala1352Gly was identified as a polymorphism predominant in individuals of African descent. Our data underscore the need for investigating RYR1 across different ethnic groups and will contribute to interpretation of genetic screening results of individuals at risk for MH.
- SourceAvailable from: Antonella Carsana
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- "c.2797G>A c.6478G>A 28 39 S1342G/ G2160S 1 cDNA complete rs34694816 rs143398211 MHS  c.7300G>A 4 5 G 2 4 3 4 R Y e s 1 gDNA hot spot rs121918593 MHS  "
ABSTRACT: Exertional rhabdomyolysis (ER) and stress-induced malignant hyperthermia (MH) events are syndromes that primarily afflict military recruits in basic training and athletes. Events similar to those occurring in ER and in stress-induced MH events are triggered after exposure to anesthetic agents in MH-susceptible (MHS) patients. MH is an autosomal dominant hypermetabolic condition that occurs in genetically predisposed subjects during general anesthesia, induced by commonly used volatile anesthetics and/or the neuromuscular blocking agent succinylcholine. Triggering agents cause an altered intracellular calcium regulation. Mutations in gene have been found in about 70% of MH families. The gene encodes the skeletal muscle calcium release channel of the sarcoplasmic reticulum, commonly known as ryanodine receptor type 1 (RYR1). The present work reviews the documented cases of ER or of stress-induced MH events in which sequence variations, associated or possibly associated to MHS status, have been identified.The Scientific World Journal 02/2013; 2013:531465. DOI:10.1155/2013/531465 · 1.73 Impact Factor
Biochimica et Biophysica Acta 08/2011; 1813(12):2193-4. DOI:10.1016/j.bbamcr.2011.08.002 · 4.66 Impact Factor
- "" She further wrote, " Although a link has never been established by controlled clinical studies, individual case reports and a small number of clinical series support an association between unexpected exertional rhabdomyolysis and MH susceptibility, two syndromes characterized by abnormal intracellular skeletal muscle calcium regulation. " The genetic basis of exertional rhabdomyolysis is an important issue for the uniformed services and Dr. Muldoon, as well as Drs Gronert, Tobin and others must be lauded for taking on the worthy cause of developing " stress-induced MH " into a viable research area within the MH field . However, any statement concerning an association between human stress and MH episodes must be made with the utmost caution since it could cause unnecessary and unjustified alarm among MH patients. "
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- "It is possible that these variants may exist in linkage disequilibrium. Sambuughin, et al.  reported the coexistence of these variants in 2 of 6 African Americans with exertional rhabdomyolysis and MHS. Patient 9 also had the K153R variant in the GDF8 gene as well as the harmless P65L polymorphism in the VLCAD gene and the common cosegregating mutations Q12X and P48L in the AMPD1 gene. "
ABSTRACT: Malignant hyperthermia (MH) is a pharmacogenetic, autosomal dominantly inherited disorder of skeletal muscle triggered by volatile anesthetics and infrequently by extreme exertion and heat exposure. MH has variable penetrance with an incidence ranging from 1 in 5000 to 1 in 50,000-100,000 anesthesias. Mutations in the ryanodine receptor gene, RYR1, are found in 50-70% of cases. We hypothesized that a portion of patients with drug-induced muscle diseases, unrelated to anesthesia, such as severe statin myopathy, have underlying genetic liability that may include RYR1 gene mutations. DNA samples were collected from 885 patients in 4 groups: severe statin myopathy (n=197), mild statin myopathy (n=163), statin-tolerant controls (n=133), and non-drug-induced myopathies of unknown etiology characterized by exercise-induced muscle pain and weakness (n=392). Samples were screened for 105 mutations and variants in 26 genes associated with 7 categories of muscle disease including 34 mutations and variants in the RYR1 gene. Disease-causing mutations or variants in RYR1 were present in 3 severe statin myopathy cases, 1 mild statin myopathy case, 8 patients with non-drug-induced myopathy, and none in controls. These results suggest that disease-causing mutations and certain variants in the RYR1 gene may contribute to underlying genetic risk for non-anesthesia-induced myopathies and should be included in genetic susceptibility screening in patients with severe statin myopathy and in patients with non-statin-induced myopathies of unknown etiology.Molecular Genetics and Metabolism 07/2011; 104(1-2):167-73. DOI:10.1016/j.ymgme.2011.07.001 · 2.83 Impact Factor