Phenotypic Mutation 'Arruda2' (pdf version)
AlleleArruda2
Mutation Type missense
Chromosome13
Coordinate11,894,382 bp (GRCm39)
Base Change G ⇒ T (forward strand)
Gene Ryr2
Gene Name ryanodine receptor 2, cardiac
Synonym(s) 9330127I20Rik
Chromosomal Location 11,567,988-12,121,831 bp (-) (GRCm39)
MGI Phenotype FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]
PHENOTYPE: Homozygous null mice show embryonic lethality during organogenesis and altered cardiomyocyte morphology. Homozygotes for a phosphorylation defective allele show decreased susceptibility to myocardial infarction-induced heart failure. Homozygotes for the R420W allele show lymphoid organ hypertrophy. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_023868; MGI:99685

MappedYes 
Amino Acid Change Serine changed to Arginine
Institutional SourceBeutler Lab
Gene Model predicted gene model for protein(s): [ENSMUSP00000021750] [ENSMUSP00000127991] [ENSMUSP00000152051]
AlphaFold no structure available at present
PDB Structure X-ray crystallography-solution NMR hybrid structure of mouse RyR2 domain A [SOLUTION NMR]
Crystal structure of mouse Ryanodine Receptor 2 (residues 1-217) [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 mutant V186M [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 N-terminal domain (1-217) disease mutant A77V [X-RAY DIFFRACTION]
Structure of the first domain of a cardiac Ryanodine Receptor mutant with exon 3 deleted [X-RAY DIFFRACTION]
Crystal structure of mouse ryanodine receptor 2 (2699-2904) [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 (1-217) disease mutant P164S [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 (1-217) disease mutant R169Q [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 (1-217) disease mutant R176Q [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor isoform 2 (RyR2) 1-547 [X-RAY DIFFRACTION]
>> 3 additional structures at PDB <<
SMART Domains Protein: ENSMUSP00000021750
Gene: ENSMUSG00000021313
AA Change: S185R

DomainStartEndE-ValueType
MIR 110 165 4.19e-2 SMART
MIR 172 217 9.25e-4 SMART
MIR 225 280 1.8e-1 SMART
MIR 286 376 2.22e-24 SMART
Pfam:RYDR_ITPR 454 648 3.1e-65 PFAM
SPRY 670 808 1.56e-30 SMART
Pfam:RyR 862 952 1.8e-36 PFAM
Pfam:RyR 976 1066 1.1e-32 PFAM
SPRY 1098 1221 5.07e-39 SMART
SPRY 1423 1562 7.47e-28 SMART
low complexity region 1643 1653 N/A INTRINSIC
low complexity region 1872 1891 N/A INTRINSIC
Pfam:RYDR_ITPR 2122 2331 1.2e-71 PFAM
low complexity region 2372 2379 N/A INTRINSIC
low complexity region 2416 2426 N/A INTRINSIC
low complexity region 2497 2510 N/A INTRINSIC
Pfam:RyR 2700 2790 1.1e-33 PFAM
Pfam:RyR 2820 2904 7.1e-27 PFAM
PDB:2BCX|B 3580 3609 9e-12 PDB
low complexity region 3700 3720 N/A INTRINSIC
Pfam:RIH_assoc 3829 3947 3.1e-36 PFAM
EFh 4026 4054 1.36e0 SMART
EFh 4061 4089 5.92e1 SMART
low complexity region 4218 4227 N/A INTRINSIC
low complexity region 4256 4273 N/A INTRINSIC
transmembrane domain 4278 4300 N/A INTRINSIC
low complexity region 4309 4317 N/A INTRINSIC
Pfam:RR_TM4-6 4332 4598 5.7e-96 PFAM
Pfam:Ion_trans 4710 4877 8e-16 PFAM
Predicted Effect probably damaging

PolyPhen 2 Score 0.997 (Sensitivity: 0.41; Specificity: 0.98)
(Using ENSMUST00000021750)
SMART Domains Protein: ENSMUSP00000127991
Gene: ENSMUSG00000021313
AA Change: S185R

DomainStartEndE-ValueType
MIR 110 165 4.19e-2 SMART
MIR 172 217 9.25e-4 SMART
MIR 225 280 1.8e-1 SMART
MIR 286 376 2.22e-24 SMART
Pfam:RYDR_ITPR 451 655 3.5e-73 PFAM
SPRY 670 808 1.56e-30 SMART
Pfam:RyR 861 955 1.4e-33 PFAM
Pfam:RyR 975 1069 9.2e-34 PFAM
SPRY 1098 1221 5.07e-39 SMART
SPRY 1423 1562 7.47e-28 SMART
low complexity region 1643 1653 N/A INTRINSIC
low complexity region 1872 1891 N/A INTRINSIC
Pfam:RYDR_ITPR 2120 2331 3.9e-65 PFAM
low complexity region 2372 2379 N/A INTRINSIC
low complexity region 2416 2426 N/A INTRINSIC
low complexity region 2497 2510 N/A INTRINSIC
Pfam:RyR 2699 2793 1.1e-37 PFAM
Pfam:RyR 2819 2907 9.4e-34 PFAM
PDB:2BCX|B 3580 3609 9e-12 PDB
low complexity region 3700 3720 N/A INTRINSIC
Pfam:RIH_assoc 3825 3958 2.3e-42 PFAM
EFh 4026 4054 1.36e0 SMART
EFh 4061 4089 5.92e1 SMART
low complexity region 4218 4227 N/A INTRINSIC
low complexity region 4256 4273 N/A INTRINSIC
transmembrane domain 4278 4300 N/A INTRINSIC
low complexity region 4309 4317 N/A INTRINSIC
Pfam:RR_TM4-6 4332 4598 5.1e-93 PFAM
Pfam:Ion_trans 4705 4865 9.3e-11 PFAM
Predicted Effect probably damaging

PolyPhen 2 Score 0.998 (Sensitivity: 0.27; Specificity: 0.99)
(Using ENSMUST00000170156)
Predicted Effect probably damaging

PolyPhen 2 Score 0.996 (Sensitivity: 0.55; Specificity: 0.98)
(Using ENSMUST00000220597)
Meta Mutation Damage Score 0.2762 question?
Is this an essential gene? Essential (E-score: 1.000) question?
Phenotypic Category Unknown
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance  
Alleles Listed at MGI

All Mutations and Alleles(56) : Gene trapped(27) Targeted(29)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00518:Ryr2 APN 13 11848978 splice site probably benign
IGL00757:Ryr2 APN 13 11633490 splice site probably null
IGL00838:Ryr2 APN 13 11583389 missense probably damaging 0.98
IGL00849:Ryr2 APN 13 11600364 missense possibly damaging 0.91
IGL00987:Ryr2 APN 13 11750388 missense probably damaging 0.99
IGL01096:Ryr2 APN 13 11718430 missense probably damaging 1.00
IGL01313:Ryr2 APN 13 11653371 critical splice acceptor site probably null
IGL01349:Ryr2 APN 13 11602125 missense possibly damaging 0.93
IGL01391:Ryr2 APN 13 11571571 missense possibly damaging 0.96
IGL01401:Ryr2 APN 13 11606238 missense possibly damaging 0.80
IGL01412:Ryr2 APN 13 11756922 missense probably benign 0.10
IGL01419:Ryr2 APN 13 11814723 missense possibly damaging 0.51
IGL01432:Ryr2 APN 13 11866090 missense possibly damaging 0.63
IGL01533:Ryr2 APN 13 11736676 missense probably damaging 1.00
IGL01571:Ryr2 APN 13 11736647 missense probably damaging 1.00
IGL01584:Ryr2 APN 13 11616644 critical splice donor site probably null
IGL01611:Ryr2 APN 13 11606202 missense possibly damaging 0.67
IGL01632:Ryr2 APN 13 11609854 missense probably damaging 0.97
IGL01643:Ryr2 APN 13 11707563 missense possibly damaging 0.94
IGL01647:Ryr2 APN 13 11600366 missense probably damaging 1.00
IGL01730:Ryr2 APN 13 11616728 missense possibly damaging 0.86
IGL01834:Ryr2 APN 13 11610311 missense possibly damaging 0.71
IGL01921:Ryr2 APN 13 11569436 missense possibly damaging 0.96
IGL01937:Ryr2 APN 13 11805249 missense probably damaging 1.00
IGL01945:Ryr2 APN 13 11805249 missense probably damaging 1.00
IGL02027:Ryr2 APN 13 11611998 missense probably damaging 1.00
IGL02060:Ryr2 APN 13 11762450 missense probably damaging 1.00
IGL02065:Ryr2 APN 13 11587143 missense possibly damaging 0.92
IGL02084:Ryr2 APN 13 11807648 nonsense probably null
IGL02086:Ryr2 APN 13 11750442 missense probably damaging 1.00
IGL02095:Ryr2 APN 13 11774645 missense probably damaging 0.98
IGL02100:Ryr2 APN 13 11752759 missense possibly damaging 0.92
IGL02122:Ryr2 APN 13 11756755 missense probably damaging 1.00
IGL02202:Ryr2 APN 13 11762544 splice site probably benign
IGL02202:Ryr2 APN 13 11745274 missense probably damaging 0.97
IGL02369:Ryr2 APN 13 11634382 missense possibly damaging 0.68
IGL02383:Ryr2 APN 13 11737607 splice site probably benign
IGL02400:Ryr2 APN 13 11620130 splice site probably benign
IGL02423:Ryr2 APN 13 11760084 missense probably damaging 1.00
IGL02425:Ryr2 APN 13 11760560 missense probably damaging 0.99
IGL02458:Ryr2 APN 13 11720585 missense probably benign 0.15
IGL02602:Ryr2 APN 13 11569397 utr 3 prime probably benign
IGL02694:Ryr2 APN 13 11620075 missense probably damaging 1.00
IGL02726:Ryr2 APN 13 11753206 missense probably damaging 1.00
IGL02747:Ryr2 APN 13 11670563 missense probably damaging 1.00
IGL02795:Ryr2 APN 13 11610076 missense probably benign 0.21
IGL02876:Ryr2 APN 13 11722679 missense probably benign 0.39
IGL02878:Ryr2 APN 13 11933205 missense probably benign 0.10
IGL02887:Ryr2 APN 13 11606155 missense probably damaging 0.97
IGL02926:Ryr2 APN 13 11774721 missense probably damaging 0.99
IGL03030:Ryr2 APN 13 11699365 missense probably damaging 0.99
IGL03064:Ryr2 APN 13 11658788 critical splice acceptor site probably null
IGL03102:Ryr2 APN 13 11650468 splice site probably benign
IGL03152:Ryr2 APN 13 11868036 missense probably damaging 1.00
IGL03176:Ryr2 APN 13 11756909 nonsense probably null
IGL03180:Ryr2 APN 13 11583449 missense possibly damaging 0.95
IGL03213:Ryr2 APN 13 11739273 splice site probably benign
IGL03390:Ryr2 APN 13 11787302 missense probably benign
IGL03410:Ryr2 APN 13 11603033 missense probably damaging 0.99
Arruda UTSW 13 11658781 missense probably damaging 1.00
Arruda3 UTSW 13 11570334 missense possibly damaging 0.91
barricuda UTSW 13 11609900 missense probably benign 0.06
BB006:Ryr2 UTSW 13 11705181 nonsense probably null
BB006:Ryr2 UTSW 13 11609680 missense probably damaging 1.00
BB016:Ryr2 UTSW 13 11705181 nonsense probably null
BB016:Ryr2 UTSW 13 11609680 missense probably damaging 1.00
H8562:Ryr2 UTSW 13 11732027 splice site probably benign
IGL02799:Ryr2 UTSW 13 11680848 missense probably damaging 1.00
IGL02991:Ryr2 UTSW 13 11776192 missense probably damaging 0.99
PIT4142001:Ryr2 UTSW 13 11722682 missense probably damaging 0.97
PIT4260001:Ryr2 UTSW 13 11609641 missense possibly damaging 0.93
PIT4458001:Ryr2 UTSW 13 11570334 missense probably benign 0.29
R0003:Ryr2 UTSW 13 11839265 missense probably damaging 1.00
R0004:Ryr2 UTSW 13 11680805 missense probably benign
R0018:Ryr2 UTSW 13 11610109 missense possibly damaging 0.94
R0048:Ryr2 UTSW 13 11610670 missense probably damaging 1.00
R0048:Ryr2 UTSW 13 11610670 missense probably damaging 1.00
R0056:Ryr2 UTSW 13 11683924 missense probably damaging 0.97
R0062:Ryr2 UTSW 13 11884002 critical splice donor site probably null
R0062:Ryr2 UTSW 13 11884002 critical splice donor site probably null
R0080:Ryr2 UTSW 13 11583361 missense probably damaging 0.98
R0116:Ryr2 UTSW 13 11724807 missense probably damaging 1.00
R0148:Ryr2 UTSW 13 11729434 missense probably damaging 1.00
R0206:Ryr2 UTSW 13 11691137 splice site probably benign
R0226:Ryr2 UTSW 13 11787442 missense probably damaging 1.00
R0285:Ryr2 UTSW 13 11731863 missense probably damaging 1.00
R0365:Ryr2 UTSW 13 11683725 missense possibly damaging 0.90
R0401:Ryr2 UTSW 13 11720570 missense probably benign 0.45
R0415:Ryr2 UTSW 13 11884042 missense probably damaging 0.97
R0418:Ryr2 UTSW 13 11848981 splice site probably benign
R0558:Ryr2 UTSW 13 11814747 missense probably damaging 1.00
R0558:Ryr2 UTSW 13 11653329 missense probably damaging 1.00
R0574:Ryr2 UTSW 13 11746555 missense probably benign 0.02
R0586:Ryr2 UTSW 13 11650445 missense probably null
R0601:Ryr2 UTSW 13 11720519 critical splice donor site probably null
R0610:Ryr2 UTSW 13 11637838 missense probably damaging 1.00
R0648:Ryr2 UTSW 13 11739219 missense possibly damaging 0.86
R0727:Ryr2 UTSW 13 11581771 missense probably damaging 1.00
R0743:Ryr2 UTSW 13 11569415 missense probably damaging 0.99
R0821:Ryr2 UTSW 13 11753012 missense probably benign 0.35
R0884:Ryr2 UTSW 13 11569415 missense probably damaging 0.99
R1104:Ryr2 UTSW 13 11684855 missense probably damaging 0.99
R1114:Ryr2 UTSW 13 11960867 missense probably damaging 0.98
R1167:Ryr2 UTSW 13 11674999 missense possibly damaging 0.94
R1238:Ryr2 UTSW 13 11774589 missense probably damaging 1.00
R1239:Ryr2 UTSW 13 11897929 critical splice donor site probably null
R1296:Ryr2 UTSW 13 11702765 splice site probably benign
R1400:Ryr2 UTSW 13 11609962 missense probably benign 0.08
R1439:Ryr2 UTSW 13 11729389 splice site probably benign
R1443:Ryr2 UTSW 13 11794152 missense probably benign 0.19
R1446:Ryr2 UTSW 13 11753035 missense probably benign 0.09
R1458:Ryr2 UTSW 13 11741908 missense probably damaging 0.97
R1497:Ryr2 UTSW 13 11616727 missense probably damaging 0.99
R1505:Ryr2 UTSW 13 11569478 missense possibly damaging 0.84
R1548:Ryr2 UTSW 13 11569435 nonsense probably null
R1551:Ryr2 UTSW 13 11800029 critical splice acceptor site probably null
R1567:Ryr2 UTSW 13 11774563 missense possibly damaging 0.87
R1581:Ryr2 UTSW 13 11809449 missense probably benign 0.01
R1645:Ryr2 UTSW 13 11733368 nonsense probably null
R1686:Ryr2 UTSW 13 11618665 splice site probably benign
R1696:Ryr2 UTSW 13 11746543 missense probably benign 0.02
R1708:Ryr2 UTSW 13 11602328 splice site probably null
R1728:Ryr2 UTSW 13 11602308 missense possibly damaging 0.94
R1745:Ryr2 UTSW 13 11805153 missense probably damaging 1.00
R1771:Ryr2 UTSW 13 11760062 critical splice donor site probably null
R1776:Ryr2 UTSW 13 11760062 critical splice donor site probably null
R1783:Ryr2 UTSW 13 11715257 nonsense probably null
R1801:Ryr2 UTSW 13 11610167 missense probably benign 0.01
R1812:Ryr2 UTSW 13 11575472 missense probably damaging 0.97
R1820:Ryr2 UTSW 13 11602202 missense probably damaging 0.99
R1835:Ryr2 UTSW 13 11784764 missense probably benign 0.06
R1868:Ryr2 UTSW 13 11746586 missense probably benign 0.02
R1869:Ryr2 UTSW 13 11676961 missense probably damaging 0.98
R1884:Ryr2 UTSW 13 11753242 missense probably damaging 0.97
R1892:Ryr2 UTSW 13 11673844 nonsense probably null
R1897:Ryr2 UTSW 13 11765818 missense probably benign 0.09
R1899:Ryr2 UTSW 13 11606222 missense probably benign
R1909:Ryr2 UTSW 13 11715235 missense probably damaging 1.00
R1918:Ryr2 UTSW 13 11571584 missense possibly damaging 0.91
R1937:Ryr2 UTSW 13 11683848 missense probably damaging 1.00
R1943:Ryr2 UTSW 13 11746609 missense probably benign 0.10
R1956:Ryr2 UTSW 13 11695966 missense probably damaging 1.00
R1983:Ryr2 UTSW 13 11600288 splice site probably null
R2018:Ryr2 UTSW 13 11866074 missense possibly damaging 0.59
R2019:Ryr2 UTSW 13 11866074 missense possibly damaging 0.59
R2060:Ryr2 UTSW 13 11610622 missense probably damaging 1.00
R2061:Ryr2 UTSW 13 11680764 splice site probably null
R2088:Ryr2 UTSW 13 11677115 missense probably benign 0.04
R2089:Ryr2 UTSW 13 11960863 missense probably benign 0.23
R2091:Ryr2 UTSW 13 11960863 missense probably benign 0.23
R2091:Ryr2 UTSW 13 11960863 missense probably benign 0.23
R2127:Ryr2 UTSW 13 11727081 missense probably damaging 1.00
R2140:Ryr2 UTSW 13 11575493 missense probably damaging 1.00
R2153:Ryr2 UTSW 13 11592759 missense possibly damaging 0.86
R2179:Ryr2 UTSW 13 11720679 nonsense probably null
R2207:Ryr2 UTSW 13 11825823 missense probably damaging 1.00
R2237:Ryr2 UTSW 13 11677146 missense probably benign 0.18
R2258:Ryr2 UTSW 13 11753102 missense possibly damaging 0.94
R2312:Ryr2 UTSW 13 11753128 missense probably damaging 1.00
R2421:Ryr2 UTSW 13 11606123 missense probably damaging 0.98
R2438:Ryr2 UTSW 13 11816734 missense probably damaging 1.00
R2483:Ryr2 UTSW 13 11774589 missense probably damaging 1.00
R2860:Ryr2 UTSW 13 11607979 missense probably damaging 0.98
R2861:Ryr2 UTSW 13 11607979 missense probably damaging 0.98
R2867:Ryr2 UTSW 13 11776235 missense probably damaging 1.00
R2867:Ryr2 UTSW 13 11776235 missense probably damaging 1.00
R3618:Ryr2 UTSW 13 11787466 critical splice acceptor site probably null
R3876:Ryr2 UTSW 13 11603045 missense probably damaging 0.99
R3906:Ryr2 UTSW 13 11753095 missense possibly damaging 0.87
R3912:Ryr2 UTSW 13 11787313 missense probably damaging 0.99
R4018:Ryr2 UTSW 13 11933300 missense probably damaging 1.00
R4114:Ryr2 UTSW 13 11707568 missense probably damaging 1.00
R4119:Ryr2 UTSW 13 11794153 missense probably benign 0.22
R4127:Ryr2 UTSW 13 11602323 missense possibly damaging 0.91
R4222:Ryr2 UTSW 13 11752759 missense possibly damaging 0.92
R4233:Ryr2 UTSW 13 11765611 missense probably benign 0.20
R4355:Ryr2 UTSW 13 11664698 missense probably benign 0.05
R4384:Ryr2 UTSW 13 11620119 missense probably damaging 0.99
R4422:Ryr2 UTSW 13 11731952 nonsense probably null
R4430:Ryr2 UTSW 13 11750413 missense probably damaging 0.98
R4624:Ryr2 UTSW 13 12121301 missense possibly damaging 0.47
R4663:Ryr2 UTSW 13 11764395 missense possibly damaging 0.47
R4665:Ryr2 UTSW 13 11765571 splice site probably null
R4668:Ryr2 UTSW 13 11608003 missense probably benign
R4677:Ryr2 UTSW 13 11721553 missense probably damaging 0.98
R4679:Ryr2 UTSW 13 11839255 missense probably benign 0.34
R4680:Ryr2 UTSW 13 11610119 missense probably benign 0.04
R4685:Ryr2 UTSW 13 11707532 missense probably damaging 1.00
R4709:Ryr2 UTSW 13 11731884 missense probably damaging 1.00
R4731:Ryr2 UTSW 13 11592795 missense possibly damaging 0.53
R4732:Ryr2 UTSW 13 11592795 missense possibly damaging 0.53
R4733:Ryr2 UTSW 13 11592795 missense possibly damaging 0.53
R4734:Ryr2 UTSW 13 11752639 missense probably damaging 0.99
R4740:Ryr2 UTSW 13 11671933 missense possibly damaging 0.95
R4801:Ryr2 UTSW 13 11702818 missense probably damaging 1.00
R4801:Ryr2 UTSW 13 11723113 missense probably damaging 1.00
R4802:Ryr2 UTSW 13 11702818 missense probably damaging 1.00
R4802:Ryr2 UTSW 13 11723113 missense probably damaging 1.00
R4804:Ryr2 UTSW 13 11731983 missense probably damaging 1.00
R4811:Ryr2 UTSW 13 11670584 missense probably damaging 0.97
R4850:Ryr2 UTSW 13 11760638 missense probably damaging 1.00
R4850:Ryr2 UTSW 13 11683706 missense probably damaging 0.99
R4880:Ryr2 UTSW 13 11767104 missense probably damaging 1.00
R4917:Ryr2 UTSW 13 11609872 missense probably damaging 0.96
R4918:Ryr2 UTSW 13 11609872 missense probably damaging 0.96
R4922:Ryr2 UTSW 13 11724849 missense probably damaging 0.99
R4933:Ryr2 UTSW 13 11960831 missense probably damaging 0.96
R4950:Ryr2 UTSW 13 11756897 missense probably damaging 1.00
R4957:Ryr2 UTSW 13 11799966 missense probably damaging 0.97
R4964:Ryr2 UTSW 13 11848878 missense probably benign 0.00
R4964:Ryr2 UTSW 13 11729497 missense possibly damaging 0.49
R4966:Ryr2 UTSW 13 11729497 missense possibly damaging 0.49
R4966:Ryr2 UTSW 13 11848878 missense probably benign 0.00
R4997:Ryr2 UTSW 13 11610192 missense probably benign 0.09
R4998:Ryr2 UTSW 13 11658781 missense probably damaging 1.00
R5033:Ryr2 UTSW 13 11602140 missense possibly damaging 0.93
R5061:Ryr2 UTSW 13 11650422 missense possibly damaging 0.74
R5062:Ryr2 UTSW 13 11715240 missense probably damaging 0.97
R5088:Ryr2 UTSW 13 11727129 nonsense probably null
R5135:Ryr2 UTSW 13 11677016 missense probably benign 0.05
R5138:Ryr2 UTSW 13 11675175 missense probably damaging 1.00
R5168:Ryr2 UTSW 13 11767207 missense probably benign
R5187:Ryr2 UTSW 13 11787338 missense probably damaging 0.99
R5197:Ryr2 UTSW 13 11653316 critical splice donor site probably null
R5262:Ryr2 UTSW 13 11787323 missense probably damaging 0.99
R5325:Ryr2 UTSW 13 11705249 missense probably damaging 0.97
R5381:Ryr2 UTSW 13 11571544 missense probably damaging 1.00
R5437:Ryr2 UTSW 13 11670599 missense probably damaging 1.00
R5477:Ryr2 UTSW 13 11720542 missense probably damaging 1.00
R5497:Ryr2 UTSW 13 11720587 missense probably null 0.15
R5509:Ryr2 UTSW 13 11760487 missense probably damaging 0.98
R5518:Ryr2 UTSW 13 11702795 missense probably benign 0.01
R5571:Ryr2 UTSW 13 11570334 missense possibly damaging 0.91
R5591:Ryr2 UTSW 13 11609900 missense probably benign 0.06
R5619:Ryr2 UTSW 13 11723088 missense probably damaging 1.00
R5630:Ryr2 UTSW 13 11616691 missense probably damaging 1.00
R5644:Ryr2 UTSW 13 11610468 missense probably damaging 0.99
R5667:Ryr2 UTSW 13 11774722 missense probably damaging 1.00
R5775:Ryr2 UTSW 13 11784848 missense probably damaging 1.00
R5836:Ryr2 UTSW 13 11618618 missense probably damaging 1.00
R5858:Ryr2 UTSW 13 11575460 missense probably damaging 0.99
R5934:Ryr2 UTSW 13 11599040 missense probably damaging 0.96
R5939:Ryr2 UTSW 13 11805218 missense probably damaging 0.99
R5941:Ryr2 UTSW 13 11702788 missense probably damaging 1.00
R5945:Ryr2 UTSW 13 11675008 missense probably damaging 1.00
R5946:Ryr2 UTSW 13 11741839 missense probably damaging 1.00
R5966:Ryr2 UTSW 13 11677124 nonsense probably null
R5974:Ryr2 UTSW 13 11729397 splice site probably null
R6104:Ryr2 UTSW 13 11814711 missense probably damaging 1.00
R6118:Ryr2 UTSW 13 11807575 missense possibly damaging 0.69
R6149:Ryr2 UTSW 13 11683903 missense probably benign
R6208:Ryr2 UTSW 13 11910106 missense probably benign 0.04
R6217:Ryr2 UTSW 13 11848964 missense probably damaging 1.00
R6230:Ryr2 UTSW 13 11674993 missense probably damaging 0.99
R6279:Ryr2 UTSW 13 11695885 missense probably damaging 0.97
R6294:Ryr2 UTSW 13 11894382 missense probably damaging 1.00
R6300:Ryr2 UTSW 13 11695885 missense probably damaging 0.97
R6350:Ryr2 UTSW 13 11776282 missense probably damaging 0.98
R6484:Ryr2 UTSW 13 11677269 missense possibly damaging 0.90
R6489:Ryr2 UTSW 13 11848893 missense probably benign 0.29
R6548:Ryr2 UTSW 13 11683707 missense probably damaging 1.00
R6591:Ryr2 UTSW 13 11609609 missense probably benign 0.01
R6623:Ryr2 UTSW 13 11724951 missense probably damaging 1.00
R6649:Ryr2 UTSW 13 11610529 missense probably damaging 0.99
R6691:Ryr2 UTSW 13 11609609 missense probably benign 0.01
R6770:Ryr2 UTSW 13 11753348 missense probably damaging 1.00
R6802:Ryr2 UTSW 13 11701852 missense probably damaging 1.00
R6809:Ryr2 UTSW 13 11741816 missense probably damaging 1.00
R6893:Ryr2 UTSW 13 11844540 missense possibly damaging 0.75
R6911:Ryr2 UTSW 13 11842445 missense possibly damaging 0.50
R6915:Ryr2 UTSW 13 11760487 missense probably damaging 1.00
R6943:Ryr2 UTSW 13 11581834 missense possibly damaging 0.92
R6960:Ryr2 UTSW 13 11816129 missense probably benign 0.28
R6997:Ryr2 UTSW 13 11669266 missense possibly damaging 0.88
R6998:Ryr2 UTSW 13 11727052 missense probably damaging 0.99
R7001:Ryr2 UTSW 13 11809491 missense probably damaging 0.98
R7047:Ryr2 UTSW 13 11839286 missense possibly damaging 0.64
R7089:Ryr2 UTSW 13 11664662 missense probably benign 0.10
R7125:Ryr2 UTSW 13 11684873 missense probably damaging 0.99
R7127:Ryr2 UTSW 13 11670599 missense probably damaging 1.00
R7131:Ryr2 UTSW 13 11683697 critical splice donor site probably null
R7131:Ryr2 UTSW 13 11655213 missense possibly damaging 0.63
R7159:Ryr2 UTSW 13 11825794 missense probably damaging 0.99
R7174:Ryr2 UTSW 13 11816063 missense possibly damaging 0.81
R7180:Ryr2 UTSW 13 11701864 missense probably damaging 1.00
R7182:Ryr2 UTSW 13 11774643 missense probably benign
R7189:Ryr2 UTSW 13 11898009 missense probably damaging 1.00
R7241:Ryr2 UTSW 13 11680799 missense possibly damaging 0.71
R7244:Ryr2 UTSW 13 11612032 missense probably damaging 1.00
R7326:Ryr2 UTSW 13 11753080 missense possibly damaging 0.95
R7331:Ryr2 UTSW 13 11760517 missense probably benign
R7365:Ryr2 UTSW 13 11655161 missense probably damaging 0.99
R7372:Ryr2 UTSW 13 11695885 missense probably damaging 0.97
R7395:Ryr2 UTSW 13 11799997 missense probably damaging 0.98
R7404:Ryr2 UTSW 13 11750506 missense probably damaging 0.97
R7417:Ryr2 UTSW 13 11571634 splice site probably null
R7425:Ryr2 UTSW 13 11720530 missense probably benign 0.20
R7444:Ryr2 UTSW 13 11570349 missense probably benign 0.25
R7456:Ryr2 UTSW 13 11767168 missense probably benign
R7460:Ryr2 UTSW 13 11720596 missense probably benign 0.10
R7474:Ryr2 UTSW 13 11609762 missense probably benign 0.04
R7543:Ryr2 UTSW 13 11653317 critical splice donor site probably null
R7549:Ryr2 UTSW 13 11752871 missense probably benign 0.15
R7558:Ryr2 UTSW 13 11814711 missense probably damaging 1.00
R7565:Ryr2 UTSW 13 11575539 missense possibly damaging 0.84
R7627:Ryr2 UTSW 13 11776213 missense possibly damaging 0.65
R7698:Ryr2 UTSW 13 11776201 missense possibly damaging 0.94
R7702:Ryr2 UTSW 13 11705219 missense probably damaging 0.99
R7719:Ryr2 UTSW 13 11745229 missense possibly damaging 0.94
R7772:Ryr2 UTSW 13 11765897 missense probably benign
R7797:Ryr2 UTSW 13 11816066 missense probably damaging 0.99
R7829:Ryr2 UTSW 13 11842493 missense possibly damaging 0.81
R7855:Ryr2 UTSW 13 11721509 nonsense probably null
R7872:Ryr2 UTSW 13 11610610 missense probably damaging 1.00
R7908:Ryr2 UTSW 13 11807634 missense probably benign 0.01
R7929:Ryr2 UTSW 13 11609680 missense probably damaging 1.00
R7929:Ryr2 UTSW 13 11705181 nonsense probably null
R7952:Ryr2 UTSW 13 11661313 splice site probably null
R8008:Ryr2 UTSW 13 11671980 missense probably benign 0.30
R8011:Ryr2 UTSW 13 11603026 critical splice donor site probably null
R8097:Ryr2 UTSW 13 11960881 missense probably damaging 0.98
R8133:Ryr2 UTSW 13 11618584 missense probably damaging 1.00
R8253:Ryr2 UTSW 13 11842439 missense possibly damaging 0.94
R8278:Ryr2 UTSW 13 11610392 nonsense probably null
R8351:Ryr2 UTSW 13 11814718 missense probably damaging 0.98
R8401:Ryr2 UTSW 13 11683821 missense possibly damaging 0.95
R8403:Ryr2 UTSW 13 11699364 missense possibly damaging 0.95
R8431:Ryr2 UTSW 13 11673894 missense probably benign 0.00
R8509:Ryr2 UTSW 13 11592664 critical splice donor site probably null
R8551:Ryr2 UTSW 13 11575479 missense possibly damaging 0.93
R8684:Ryr2 UTSW 13 11702875 missense probably damaging 0.99
R8735:Ryr2 UTSW 13 11701833 missense probably damaging 0.97
R8766:Ryr2 UTSW 13 11683855 missense probably damaging 0.97
R8817:Ryr2 UTSW 13 11750509 missense possibly damaging 0.95
R8827:Ryr2 UTSW 13 11572934 missense possibly damaging 0.80
R8884:Ryr2 UTSW 13 11794152 missense probably benign 0.19
R8889:Ryr2 UTSW 13 11799990 missense probably damaging 0.99
R8891:Ryr2 UTSW 13 11814768 missense probably damaging 1.00
R8979:Ryr2 UTSW 13 11609924 missense probably benign 0.00
R9013:Ryr2 UTSW 13 11618618 missense probably damaging 0.98
R9040:Ryr2 UTSW 13 11609672 missense probably damaging 0.97
R9044:Ryr2 UTSW 13 11752989 nonsense probably null
R9056:Ryr2 UTSW 13 11610817 missense possibly damaging 0.94
R9084:Ryr2 UTSW 13 11616724 missense probably damaging 1.00
R9113:Ryr2 UTSW 13 11618741 intron probably benign
R9116:Ryr2 UTSW 13 11587185 missense possibly damaging 0.93
R9125:Ryr2 UTSW 13 11669292 missense probably benign 0.28
R9148:Ryr2 UTSW 13 11900424 missense probably benign 0.02
R9210:Ryr2 UTSW 13 11844560 missense probably damaging 0.99
R9212:Ryr2 UTSW 13 11844560 missense probably damaging 0.99
R9233:Ryr2 UTSW 13 11610772 missense possibly damaging 0.77
R9254:Ryr2 UTSW 13 11898002 missense probably damaging 1.00
R9262:Ryr2 UTSW 13 11765854 missense probably damaging 0.97
R9275:Ryr2 UTSW 13 11897976 missense probably benign 0.10
R9278:Ryr2 UTSW 13 11897976 missense probably benign 0.10
R9309:Ryr2 UTSW 13 11721578 missense probably damaging 0.99
R9379:Ryr2 UTSW 13 11898002 missense probably damaging 1.00
R9409:Ryr2 UTSW 13 11695973 missense probably damaging 0.99
R9429:Ryr2 UTSW 13 11809459 missense probably damaging 0.97
R9445:Ryr2 UTSW 13 11787463 missense probably damaging 1.00
R9464:Ryr2 UTSW 13 11752680 missense probably benign 0.00
R9467:Ryr2 UTSW 13 11571490 missense possibly damaging 0.70
R9546:Ryr2 UTSW 13 11602101 critical splice donor site probably null
R9562:Ryr2 UTSW 13 11760104 missense probably damaging 1.00
R9609:Ryr2 UTSW 13 11683848 missense probably damaging 1.00
R9704:Ryr2 UTSW 13 11737646 missense probably damaging 1.00
R9764:Ryr2 UTSW 13 11701935 missense possibly damaging 0.67
R9772:Ryr2 UTSW 13 11609785 missense probably benign 0.13
R9776:Ryr2 UTSW 13 11707599 missense probably damaging 0.98
S24628:Ryr2 UTSW 13 11884042 missense probably damaging 0.97
X0019:Ryr2 UTSW 13 11718387 missense probably benign 0.04
Z1176:Ryr2 UTSW 13 11658689 critical splice donor site probably null
Z1176:Ryr2 UTSW 13 11613497 critical splice acceptor site probably null
Z1176:Ryr2 UTSW 13 11809435 nonsense probably null
Z1177:Ryr2 UTSW 13 11765759 missense possibly damaging 0.87
Mode of Inheritance Unknown
Local Stock
Repository
Last Updated 2019-10-29 9:58 AM by Anne Murray
Record Created 2018-07-13 7:12 PM by Bruce Beutler
Record Posted 2018-10-24
Phenotypic Description

Figure 1. Arruda2 mice exhibited reduced heart rates. Normalized day 2 testing results shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

The Arruda2 phenotype was identified among G3 mice of the pedigree R6294, some of which showed reduced heart rates compared to wild-type littermates (Figure 1).

Nature of Mutation

Figure 2. Linkage mapping of the reduced heart rates using an additive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 72 mutations (X-axis) identified in the G1 male of pedigree R6294. Normalized phenotype data are shown for single locus linkage analysis without consideration of G2 dam identity. Horizontal pink and red lines represent thresholds of P = 0.05, and the threshold for P = 0.05 after applying Bonferroni correction, respectively.

Whole exome HiSeq sequencing of the G1 grandsire identified 72 mutations. The heart rate phenotype was linked by continuous variable mapping to a mutation in Ryr2:  a C to A transversion at base pair 11,879,496 (v38) on chromosome 13, or base pair 227,450 in the GenBank genomic region NC_000079. Linkage was found with an additive model of inheritance, wherein three variant homozygotes and 26 heterozygous mice departed phenotypically from 23 homozygous reference mice with a P value of 2.127 x 10-7 (Figure 2).  

The mutation corresponds to residue 1,054 in the mRNA sequence NM_023868 within exon 8 of 105 total exons.

1037 GATCTCATCTTGGTCAGCGTGTCCTCAGAAAGG

180  -D--L--I--L--V--S--V--S--S--E--R-

The mutated nucleotide is indicated in red. The mutation results in a serine to arginine substitution at position 185 (S185R) in the RYR2 protein, and is strongly predicted by Polyphen-2 to cause loss of function (score = 0.997).

Illustration of Mutations in
Gene & Protein
Protein Prediction
Figure 3. The RYR2 protein. A. Domain organization of RYR2. The Arruda2 mutation results in a serine to arginine substitution at position 185 in subdomain A. B. Topology of the RYR2 protein. Two monomers of the RYR homotetramer are shown. NTD, N-terminal domain; LZ, Luecine zipper; EF, EF hand domain; TM, Transmembrane; PF, Pore-forming; CTD, C-terminal domain. This image in interactive. Other mutations found in the RYR2 protein are noted in red. Click on each mutation for more information.

Ryr2 encodes cardiac ryanodine receptor 2 (RYR2). RYR2 has a large (amino acids 1 to 4,231) cytoplasmic N-terminal tail, six transmembrane domains, and a short C-terminal tail (amino acids 4,870 to 4,966). The luminal loops of the RyR2 monomers contribute to the pore structure and amino acids Glu4832, Ile4829, Gly4826, and Gln4881 (rabbit RYR2) directly mediate Ca2+ passage through the pore (1-3). RYR2 has an N-terminal domain, three SPRY domains, four armadillo repeat-containing domains (termed the Handle domain), five MIR domains, two RyR domains (alternatively P1 and P2 domains), three leucine zippers, and two putative EF-hand motifs (4-8). The three-dimensional structure of the N-terminal domain contains three subdomains: A (alternatively, Pfam domain: Ins145_P3_rec; amino acids 1 to 217), B (alternatively, Pfam domain: MIR; amino acids 218 to 409), and C (alternatively, Pfam domain: RIH; amino acids 410 to 543) (7;9).

The Arruda2 mutation results in a serine to arginine substitution at position 185 (S185R); Ser185 is within the first MIR domain (in subdomain A). MIR domains are found in protein O-mannosyltransferases, inositol trisphosphate receptors, and RYR proteins. The MIR domains putatively participate in the structure of the clamp domain (10) and subdomain A is involved in channel termination.

Please see the record Arruda for more information about Ryr2.

Putative Mechanism

RYR2-associated Ca2+ release is required for cardiac muscle excitation-contraction coupling [(11;12); reviewed in (13)]. In cardiac muscle, depolarization of the plasma membrane activates Ca2+ influx via the L-type Ca2+ channel (Cav1.2; see the record hera for more information about voltage-dependent calcium channels), which subsequently activates RYR2 (14). Calcium sensors within RYR2 bind calcium and facilitate opening of the channel, resulting in release of calcium from the sarcoplasmic reticulum via the Ca2+-induced Ca2+-release (CICR) mechanism (13;15). The CICR mechanism causes a transitory increase in intracellular Ca2+ that binds to troponin C, enabling actin-myosin binding and signaling contractile myofilaments to generate force, sarcomere shortening, and myocardial contraction. Termination of sarcoplasmic reticulum Ca2+ release promotes relaxation. During relaxation, Ca2+ returns to diastolic Ca2+ levels via the activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a and the sarcolemma Na+/Ca2+ exchanger (NCX) [reviewed in (16)].

Mutations in RYR2 are linked to arrhythmogenic right ventricular dysplasia 2 [ARVD2; OMIM: #600996; (17;18)] and catecholaminergic polymorphic ventricular tachycardia 1 [CPVT1; OMIM: #604772; (19;20)]. ARVD2 is characterized by partial degeneration of the myocardium of the right ventricle, effort-induced polymorphic ventricular tachycardias, and sudden death. CPVT1 is characterized by a reproducible form of polymorphic ventricular tachycardia induced by physical activity, stress, or catecholamine infusion, which can deteriorate into ventricular fibrillation. Patients exhibit recurrent syncope, seizures, or sudden death after physical activity or emotional stress; the heart is morphologically normal.

Several mouse Ryr2 mutant mouse strains have been generated and characterized. Most homozygous mutants were embryonic lethal. Heterozygous mutant mice (or homozygotes that were not embryonic lethal) showed heart rhythm abnormalities due to aberrant channel function, and some mutations resulted in sudden death of the mouse (21-41).

The phenotype of the Arruda2 mice mimics that of other Ryr2 mutant mice, indicating loss of RYR2-associated function.

Primers PCR Primer
Arruda2_pcr_F: GGAAGCCTGCTCAAACAGAC
Arruda2_pcr_R: TTCTGAACGTCCCTTGAGTGG

Sequencing Primer
Arruda2_seq_F: TGCTCAAACAGACCCAGGGAG
Arruda2_seq_R: GTCCCTTGAGTGGCGTCATC
Genotyping

PCR program

1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40x
6) 72°C 10:00
7) 4°C hold


The following sequence of 416 nucleotides is amplified (chromosome 13, - strand):


1   ttctgaacgt cccttgagtg gcgtcatctg gagagggaat ggatcttcaa ttaactgggt
61  tttctccatg ttttaattct ataattcgca ggggaggctt gctggtggac catacatcct
121 gcctctaagc agagatcaga aggagaaaaa gtgcgtgttg gagatgatct catcttggtc
181 agcgtgtcct cagaaaggta cttggtaagt gtggggacat ggcttcatgc ttgatgctct
241 gctgagagcg ggagatgaag tgatgcttgg taggaaatgt gcttatgagc aagcaaagct
301 agggagacaa ttcataaagg cttgtgcctc tagctataaa taactcctga gaagagaggg
361 agatgtctgt ggccttacgg ggagatggct ccctgggtct gtttgagcag gcttcc


Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.

References
Science Writers Anne Murray
Illustrators Diantha La Vine
AuthorsRoberto Pontes, Samantha Teixeira, and Bruce Beutler