Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families.

Robinson, Rachel; Curran, Julie; Hall, William J.; Halsall, P.J.; Hopkins, Phil; Markham, Alex F.; Stewart, A.; West, Sarah P.; Ellis, F. R.

doi:10.1136/jmg.35.3.196

Cited by 34 publications

(14 citation statements)

References 20 publications

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“…In no family was more than one mutation identified, and none of the mutations was identified on screening 200 MHN controls. These data suggest that further functional RYR1 mutations associated with MH susceptibility remain to be identified, as >50% MH cases demonstrate linkage to RYR1 [Robinson et al, 1998], and that defects at other loci are likely to occur. This evidence thus supports the allelic and locus heterogeneity that is now well documented for MH [Deufel et al, 1992;Deufel et al, 1995;Fagerlund et al, 1997a,b].…”

Section: Discussionmentioning

confidence: 99%

“…CCD is also heterogeneous with at least two loci identified [Kausch et al, 1991;Fananapazir et al, 1993]. The gene encoding the skeletal muscle ryanodine receptor (RYR1 on chromosome 19q13.1; MIM# 180901) plays a major role in MH, accounting for >50% of cases [Robinson et al, 1998], and has been associated with the majority of CCD cases reported. At least 24 mutations in RYR1 have been described in association with MH [Gillard et al, 1991[Gillard et al, , 1992Quane et al, 1993Quane et al, , 1994aQuane et al, ,b, 1997Zhang et al, 1993;Keating et al, 1994Keating et al, , 1997Phillips et al, 1994;Lynch et al, 1997Lynch et al, , 1999McCarthy et al, 2000;Sambuughin et al, 2001].…”

Section: Introductionmentioning

confidence: 99%

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RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes

et al. 2002

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Malignant hyperthermia (MH) and central core disease (CCD) are autosomal dominant disorders of skeletal muscle. Susceptibility to MH is only apparent after exposure to volatile anesthetics and/or depolarizing muscle relaxants. CCD patients present with diffuse muscular weakness but are also at risk of MH. Mutations in RYR1 (19q13.1), encoding a skeletal muscle calcium release channel (ryanodine receptor), account for the majority of MH and CCD cases. Fifteen RYR1 N-terminal mutations are considered causative of MH susceptibility, five of which are also associated with CCD. In the first extensive UK population survey, eight of 15 mutations were detected in 85 out of 297 (29%) unrelated MH susceptible cases, with G2434R detected in 53 cases (18%). Mutation type was shown to affect significantly MH phenotypes (in vitro contracture test (IVCT) response to caffeine, halothane, and ryanodine). RYR1 mutations associated with both CCD and MH (R163C, R2163H, R2435H) had more severe caffeine and halothane response phenotypes than those associated with MH alone. Mutations near the amino terminal (R163C, G341R) had a relatively greater effect on responses to caffeine than halothane, with a significantly increased caffeine:halothane tension ratio compared to G2434R of the central domain. All phenotypes were more severe in males than females, and were also affected by muscle specimen size and viability. Discordance between RYR1 genotype and IVCT phenotype was observed in seven families (nine individuals), with five false-positives and four false-negatives. This represents the most extensive study of MH patient clinical and genetic data to date and demonstrates that RYR1 mutations involved in CCD are those associated with one end of the spectrum of MH IVCT phenotypes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes

et al. 2002

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“…142 If the 8 familes with one recombinant were indeed linked to MHS-1, this study would suggest that more than 85% of the families are linked to RYR1. Examples of families with false IVCT results have been reported 61,97,148 and as mutational screening progresses, judgment of quality of the IVCT based on genetic data will be enabled.…”

Section: Secondary Locimentioning

confidence: 97%

Genetics and pathogenesis of malignant hyperthermia

2000

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Malignant hyperthermia (MH) is a potentially life-threatening event in response to anesthetic triggering agents, with symptoms of sustained uncontrolled skeletal muscle calcium homeostasis resulting in organ and systemic failure. Susceptibility to MH, an autosomal dominant trait, may be associated with congenital myopathies, but in the majority of the cases, no clinical signs of disease are visible outside of anesthesia. For diagnosis, a functional test on skeletal muscle biopsy, the in vitro contracture test (IVCT), is performed. Over 50% of the families show linkage of the IVCT phenotype to the gene encoding the skeletal muscle ryanodine receptor and over 20 mutations therein have been described. At least five other loci have been defined implicating greater genetic heterogeneity than previously assumed, but so far only one further gene encoding the main subunit of the voltage-gated dihydropyridine receptor has a confirmed role in MH. As a result of extensive research on the mechanisms of excitation-contraction coupling and recent functional characterization of several disease-causing mutations in heterologous expression systems, much is known today about the molecular etiology of MH.

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“…Rare cases of mutations in the α1 subunit of the DHPR gene (CACNA1S: MIM# 114208) have been reported in MH patients Stewart et al, 2001]. Additional loci have also been linked to MH, but causative genes have still to be identified [Levitt et al, 1992;Iles et al, 1994;Sudbrak et al, 1995;Robinson et al, 1998]. In recent years, more than 60 mutations in RYR1 have been identified in MH/CCD families [Hamilton, 2005].…”

Section: Introductionmentioning

confidence: 99%

Frequency and localization of mutations in the 106 exons of theRYR1 gene in 50 individuals with malignant hyperthermia

et al. 2006

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Communicated by Maria Rita Passos-BuenoMalignant hyperthermia (MH) is a dominantly inherited pharmacogenetic condition that manifests as a life-threatening hypermetabolic reaction when a susceptible individual is exposed to common volatile anesthetics and depolarizing muscle relaxants. Although MH appears to be genetically heterogeneous, RYR1 is the main candidate for MH susceptibility. However, since molecular analysis is generally limited to exons where mutations are more frequently detected, these are routinely found only in 30-50% of susceptible subjects. In this study the entire RYR1 coding region was analyzed in a cohort of 50 Italian MH susceptible (MHS) subjects. Thirty-one mutations, 16 of which were novel, were found in 43 individuals with a mutation detection rate of 86%, the highest reported for RYR1 in MH so far. These data provide clear evidence that mutations in the RYR1 gene are the predominant cause of MH.

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Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families.

Cited by 34 publications

References 20 publications

RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes

RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes

Genetics and pathogenesis of malignant hyperthermia

Frequency and localization of mutations in the 106 exons of theRYR1 gene in 50 individuals with malignant hyperthermia

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