Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study

Klingler, Werner; Heiderich, Sebastian; Girard, Thierry; Gravino, Elvira; Heffron, James JA; Johannsen, Stephan; Jurkat-Rott, Karin; Rüffert, Henrik; Schuster, Frank; Snoeck, Marc; Sorrentino, Vincenzo; Tegazzin, Vincenzo; Lehmann-Horn, Frank

doi:10.1186/1750-1172-9-8

Orphanet Journal of Rare Diseases

Table 2 Mutations of ryanodine receptor type 1

From: Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study

				In vitro contracture test
				Contracture	Threshold
Exon	Nucleotide	Substitution	No. of patients in this study	2 vol% halothane [mN]	2 mmoll^-1caffeine [mN]	Halothane [vol%]	Caffeine [mmoll^-1]	Clinical grading scale	Causative mutation?	PolyPhen2 predictions	Sift predictions	Mutation Taster predictions	Reference
2	c.130C>T	p.R44C	1	12.0	10.8	0.5	1.0	78.0	No				Tammaro et al. 2003 [28]
3	c.178G>T	p.D60Y	1	13.0	4.5	1.0	2.0	30.0	No	+	+	+	This study, V. Sorrentino
11	c.1021G>A	p.G341R	3	14.3 ± 4.8	13.7 ± 3.1	0.8 ± 0.2	0.8 ± 0.5	54.3 ± 4.9	Yes				Quane et al. 1994 [29]
11	c.1024G>A	p.E342K	1	37.8	23.8	0.5	0.5	30.0	No	+	+	+	This study, K. Jurkat-Rott
11	c.1100G>A	p.R367Q	1	10.0	4.1	0.5	1.5	15.0	No				Galli et al. 2006 [30]
12	c.1201C>T	p.R401C	1	17.0	7.0	1.0	1.5	18.0	No				Davis et al. 2002 [31]
12	c.1202G>A	p.R401H	1	21.0	12.0	1.0	1.5	55.0	No				Rüffert et al. 2002 [32]
15	c.1655G>A	p.R552Q*	1	36.0	8.0	0.5	1.5	38.0	No	+	-	+	This study, V. Sorrentino
17	c.1840C>T	p.R614C	25	13.7 ± 8.9	10.5 ± 8.3	0.9 ± 0.5	1.3 ± 0.7	50.8 ± 22.3	Yes				Gillard et al. 1992 [33]
17	c.1841G>T	p.R614L	2	16.6 ± 2.6	8.3 ± 2.3	0.5 ± 0.0	1.0 ± 0.5	30.5 ± 2.5	Yes				Quane et al. 1997 [34]
34	c.5011G>A	p.A1671T	1	8.0	24.8	2.0	0.5	35.0	No	+	+	-	This study, K. Jurkat-Rott
38	c.6178G>T	p.G2060C*	1	16.4	8.0	0.5	1.0	88.0	No				Robinson et al. 2006 [6]
39	c.6377G>A	p.R2126Q	1	26.8	8.8	0.5	2.0	35.0	No				Kraeva et al. 2011 [7]
39	c.6387C>G	p.D2129E	1	10.0	11.0	2.0	1.0	45.0	No				Rüffert et al. 2001 [35]
39	c.6488G>C	p.R2163P	1	20.0	4.0	1.0	2.0	55.0	No				Robinson et al. 2006 [6]
39	c.6502G>A	p.V2168M	6	22.5 ± 7.1	12.3 ± 5.0	0.5 ± 0.0	1.1 ± 0.3	58.8 ± 20.5	Yes				Manning et al. 1998 [36]
40	c.6599C>T	p.A2200V	1	-	3.0	-	2.0	10.0	No				Sambuughin et al. 2005 [37]
40	c.6617C>T	p.T2206M	9	20.5 ± 10.7	10.4 ± 4.9	0.9 ± 0.4	1.0 ± 0.4	50.4 ± 16.2	Yes				Manning et al. 1998 [36]
41	c.6710G>A	p.C2237Y	1	6.0	6.0	0.5	1.0	38.0	No	+	+	+	This study, M. Snoeck
43	c.7007G>A	p.R2336H	4	12.8 ± 4.5	11.7 ± 6.1	0.8 ± 0.3	1.1 ± 0.2	47.3 ± 4.4	No				Levano et al. 2009 [38]
43	c.7025A>G	p.N2342S	1	3.0	0.0	2.0	4.0	30.0	No				Marchant et al. 2004 [39]
44	c.7034G>C	p.S2345T	1	32.0	24.0	0.5	1.0	28.0	No	(+)	-	+	This study, V. Sorrentino
44	c.7048G>A	p.A2350T	1	22.0	9.0	1.0	1.0	55.0	Yes				Sambuughin et al. 2001 [40]
44	c.7076G>A	p.R2359Q	1	3.0	4.0	2.0	2.0	15.0	No	(+)	-	+	This study, H. Rüffert
44	c.7085A>G	p.E2362G	1	16.0	8.0	0.5	1.0	43.0	No				Galli et al. 2006 [30]
44	c.7112A>G	p.E2371G	1	16.0	10.0	1.0	1.5	91.0	No				Zullo et al. 2009 [26]
44	c.7124G>C	p.G2375A	2	19.5 ± 0.5	20.5 ± 1.5	0.5 ± 0.0	0.8 ± 0.3	59.5 ± 11.5	Yes				Rüffert et al. 2002 [41]
45	c.7300G>A	p.G2434R	5	24.3 ± 14.4	12.2 ± 8.2	0.7 ± 0.2	1.1 ± 0.6	57.4 ± 19.9	Yes				Sambuugghin et al. 2001 [42]
46	c.7354C>T	p.R2452W	1	8.0	20.0	1.0	1.5	48.0	No				Chamley et al. 2000 [43]
46	c.7358T>C	p.I2453T	1	7.0	7.0	1.0	1.5	63.0	No				Rüffert et al. 2002 [41]
46	c.7360C>T	p.R2454C	1	9.2	6.0	0.5	1.0	28.0	Yes				Brandt et al. 1999 [44]
46	c.7361G>A	p.R2454H	3	15.3 ± 5.7	13.0 ± 6.5	0.8 ± 0.2	1.0 ± 0.4	48.0 ± 12.2	Yes				Barone et al. 1999 [45]
46	c.7372C>T	p.R2458C	2	7.3 ± 1.3	2.0 ± 1.0	1.0 ± 0.0	2.0 ± 0.0	41.5 ± 31.5	Yes				Manning et al. 1998 [46]
71	c.10616G˃A	p.R3539H	1	7.0	8.0	2.0	1.5	38.0	No				Dekomien et al. 2005 [47]
85	c.11708G>A	p.R3903Q	2	4.8 ± 0.2	2.5 ± 0.5	2.0 ± 0.0	2.0 ± 0.0	25.0 ± 5.0	No				Galli et al. 2006 [30]
85	c.11723A>T	p.N3908I	1	8.0	4.8	1.0	1.5	20.0	No	+	+	+	This study, K. Jurkat-Rott
90	c.12398A>G	p.E4133G	1	2.0	2.5	2.0	2.0	10.0	No	+	+	+	This study, V. Sorrentino
90	c.12413T>C	p.I4138T	1	11.0	15.0	1.0	1.0	25.0	No				Robinson et al. 2006 [6]
90	c.12532G>A	p.G4178S	1	32.0	8.0	0.5	1.5	38.0	No	+	+	+	This study, V. Sorrentino
95	c.13990T>C	p.C4664R	1	20.0	4.0	1.5	1.5	50.0	No				Zullo et al. 2009 [26]
98	c.14204G>A	p.R4735Q	1	7.0	5.0	1.0	1.5	50.0	No	+	-	+	This study, H. Rüffert
101	c.14545G>A	p.V4849I	3	3.8 ± 3.1	3.3 ± 0.8	1.5 ± 0.5	2.0 ± 0.0	36.3 ± 8.5	No				Jungbluth et al. 2002 [48]
101	c.14627A>G	p.K4876R	1	14.0	14.0	0.5	0.5	48.0	No				Monnier et al. 2005 [49]
103	c.14833C>T	p.R4945X	1	9.9	23.3	0.5	0.5	15.0	No	na	na	+	This study, K. Jurkat-Rott
106	c.15059G>C	p.W5020S	1	1.0	2.0	-	2.0	43.0	No	+	+	+	This study, V. Sorrentino

Overview of all ryanodine receptor type 1 (RyR1) mutations that have been detected in this study. If more than one patient carried the same mutation results of in vitro contracture tests (IVCT) and clinical grading scales are shown as mean ± standard deviation. Patients with double RyR1 mutations are listed separately. Novel variations (n = 13) are highlighted (bold). Polymorphisms (n = 2) are marked with asterisks (*). Polyphen2: + = probably damaging, (+) = possibly damaging, - = benign, na = not applicable to truncations; Sift: + = deleterious, - = tolerated, na = not applicable to truncations; Mutation taster: + = disease-causing; - = polymorphism.

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ISSN: 1750-1172

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