Phenotypes associated with this allele

• Allele Symbol: Ryr1⁺
• Allele Name: wild type
• Allele ID: MGI:2432648
• Summary: 10 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
ht1	Ryr1^m1Nisw/Ryr1^+	129S1.B6-Ryr1^m1Nisw	MGI:5749228
ht2	Ryr1^em1Zor/Ryr1^+	C57BL/6J-Ryr1^em1Zor	MGI:7626249
ht3	Ryr1^em2Zor/Ryr1^+	C57BL/6J-Ryr1^em2Zor	MGI:7626251
ht4	Ryr1^tm1b(EUCOMM)Hmgu/Ryr1^+	C57BL/6N-Ryr1^tm1b(EUCOMM)Hmgu/H	MGI:5797788
ht5	Ryr1^tm3.1Alle/Ryr1^+	involves: 129 * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:6515830
ht6	Ryr1^tm2.1Alle/Ryr1^+	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:4887395
ht7	Ryr1^tm1.1Inp/Ryr1^+	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5314375
ht8	Ryr1^tm1.1Dhm/Ryr1^+	involves: 129S2/SvPasCrl * 129S6/SvEvTac	MGI:4881413
ht9	Ryr1^tm1Slh/Ryr1^+	involves: 129S7/SvEvBrd * C57BL/6	MGI:3620044
ht10	Ryr1^em1Tmur/Ryr1^+	Not Specified	MGI:7260233

Genotype
MGI:5749228

ht1

• Allelic Composition: Ryr1^m1Nisw/Ryr1⁺
• Genetic Background: 129S1.B6-Ryr1^m1Nisw

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

behavior/neurological

decreased grip strength ( J:219285 )

• decrease in grip strength

• decreased hang time in wire hanging test

cellular

abnormal mitochondrial shape ( J:219285 )

• irregularly shaped mitochondria found in muscle fibers

abnormal mitochondrial physiology ( J:219285 )

• ATP content is decreased by 30% in soleus muscle

homeostasis/metabolism

abnormal potassium ion homeostasis ( J:219285 )

• intracellular potassium concentrations are decreased in soleus muscle fibers as compared to wild-type

• increased potassium ion permeability (potassium leak) in muscle of 2 month old mice

• increase in K_ATP channel activity

increased circulating potassium level ( J:219285 )

• increase in K⁺ serum levels in 6 month, but not 2 month, old mice

muscle

abnormal sarcomere morphology ( J:219285 )

• sarcomeric degeneration

abnormal Z line morphology ( J:219285 )

• increased number of z-line streaming sites observed in soleus muscle from 2 month old mice

abnormal sarcoplasmic reticulum morphology ( J:219285 )

• impaired release of Ca²⁺ from the sarcoplasmic reticulum

• increased levels of Ca²⁺ in the sarcoplasmic reticulum

• decreased myoplasmic Ca²⁺ levels

abnormal skeletal muscle fiber morphology ( J:219285 )

• core like structures observed in vastus lateralis adductor magnus and soleus muscles from 1 yr old mice

• decrease in mitochondrial activity as assessed by COX staining observed in vastus lateralis muscles from 1 yr old mice

• enlarged T-tubules in type 1 fibers observed in soleus muscle from 2 month old mice

• myofibers exhibit internalized nuclei

centrally nucleated skeletal muscle fibers ( J:219285 )

• centrally located nuclei observed in vastus lateralis, adductor magnus and soleus muscles from 1 yr old mice

muscle weakness ( J:219285 )

myopathy ( J:219285 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
congenital myopathy 1A		DOID:3529	OMIM:117000	J:219285

Genotype
MGI:7626249

ht2

• Allelic Composition: Ryr1^em1Zor/Ryr1⁺
• Genetic Background: C57BL/6J-Ryr1^em1Zor

muscle

muscle phenotype ( J:275501 , J:291685 )

N • normal fast to slow fiber ratio in extensor digitorum longus (EDL) and soleus muscles (J:275501)

N • normal wet weight of extensor digitorum longus (EDL) and soleus muscles (J:275501)

N • normal single electrical-pulse-induced mean force in extraocular muscle (J:291685)

N • normal extraocular muscle length, weight and cross section (J:291685)

abnormal skeletal muscle fiber triad morphology ( J:275501 )

• fewer calcium release units (CRUs) in extensor digitorum longus (EDL) fibers; greater percentage of dyads and CRUs absent from some EDL muscle fiber cores

skeletal muscle fiber degeneration ( J:275501 )

• atrophy of fast fibers in extensor digitorum longus (EDL) muscle as indicated by reduction of minimal Ferets fiber diameter

• normal in soleus muscle

muscle weakness ( J:275501 )

• 20% and 30% decrease of specific twitch peak force in extensor digitorum longus (EDL) and soleus muscles, respectively, after application of single action potential

• 23% reduction in maximal specific tetanic force in extensor digitorum longus (EDL) and soleus muscles after application of 50/100/120/150 Hz train of action potentials

vision/eye

vision/eye phenotype ( J:291685 )

N • normal visual acuity

behavior/neurological

decreased locomotor activity ( J:275501 )

• 25% decrease in voluntary activity (running distance) and lower median cruise speed on running wheel

homeostasis/metabolism

abnormal calcium ion homeostasis ( J:275501 )

• 15% reduction in peak Ca2+ transients induced by single action potential in extensor digitorum longus (EDL) muscle fibers

• 20% reduction in peak Ca2+ transients induced by 100 Hz action potential train in extensor digitorum longus (EDL) and soleus muscle fibers

• normal resting Ca2+ concentrations in extensor digitorum longus (EDL) and soleus muscle fibers

• normal peak Ca2+ transients induced by single action potential in soleus muscle fibers

growth/size/body

growth/size/body region phenotype ( J:275501 , J:292405 )

N • normal body weight and growth after birth (J:275501)

N • normal body weight and growth after birth (J:292405)

embryo

embryo phenotype ( J:275501 , J:292405 )

N • normal embryonic development (J:275501)

N • normal embryonic development (J:292405)

Genotype
MGI:7626251

ht3

• Allelic Composition: Ryr1^em2Zor/Ryr1⁺
• Genetic Background: C57BL/6J-Ryr1^em2Zor

muscle

muscle phenotype ( J:291685 )

• normal single electrical-pulse-induced mean force in extraocular muscle

• normal extraocular muscle length, weight and cross section

embryo

embryo phenotype ( J:292405 )

• normal embryonic development

vision/eye

vision/eye phenotype ( J:291685 )

• normal visual acuity

growth/size/body

growth/size/body region phenotype ( J:292405 )

• normal body weight and growth after birth

Genotype
MGI:5797788

ht4

• Allelic Composition: Ryr1^{tm1b(EUCOMM)Hmgu}/Ryr1⁺
• Genetic Background: C57BL/6N-Ryr1^{tm1b(EUCOMM)Hmgu}/H
• Cell Lines: HEPD0727_2_D11

Data Sources

IMPC Data for Ryr1

growth/size/body

increased spleen weight ( J:211773 )

♀

IMPC - HAR

hematopoietic system

increased spleen weight ( J:211773 )

♀

IMPC - HAR

immune system

increased spleen weight ( J:211773 )

♀

IMPC - HAR

Genotype
MGI:6515830

ht5

• Allelic Composition: Ryr1^tm3.1Alle/Ryr1⁺
• Genetic Background: involves: 129 * 129S1/Sv * 129X1/SvJ * C57BL/6

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:303297 )

• exposure to increased environmental temperature triggers fulminant heat stroke resulting in death, with a mean time to death of 68.6 minutes

homeostasis/metabolism

abnormal body temperature homeostasis ( J:303297 )

• exposure to increased environmental temperature triggers fulminant heat stroke resulting in death, with a mean time to death of 68.6 minutes and maximum temperature reached at 41.8 degrees C

increased physiological sensitivity to xenobiotic ( J:303297 )

• mice exposed to halothane exhibit a 1.8-fold and 1.4-fold elevation of intracellular calcium and sodium, respectively in vastus lateralis muscle

• mice exposed to isoflurane exhibit a 2-fold and 1.7-fold elevation of intracellular calcium and sodium, respectively in vastus lateralis muscle

• myotubes in vitro show increased sensitivity to halothane

increased susceptibility to malignant hyperthermia ( J:303297 )

• mice exhibit increased sensitivity to halothane, with a mean time to death of 65.2 minutes and their mean maximum temperature of 42.5 degrees C compared to 100% survival of wild-type mice with a mean ending temperature at 70 min of 37 degrees C

muscle

abnormal muscle physiology ( J:303297 )

• the normalized half-maximal effective concentration for intracellular calcium release in myotubes in response to KCl and caffeine are decreased

• in vivo quiescent muscle fibers of the vastus lateralis show increased intracellular calcium and sodium concentrations

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
malignant hyperthermia		DOID:8545	OMIM:PS145600	J:303297

Genotype
MGI:4887395

ht6

• Allelic Composition: Ryr1^tm2.1Alle/Ryr1⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

respiratory system

increased pulmonary respiratory rate ( J:168222 )

• resulting from halothane anesthesia

• rate increase from 147 to about 183 breaths per minute

homeostasis/metabolism

increased susceptibility to malignant hyperthermia ( J:168222 )

• hyperthermia followed by death during "recovery" period after halothane anesthesia

• pretreatment with muscle relaxants (dantrolene) eliminates symptoms of malignant hyperthermia during and following halothane exposure

• response to 42C exposure is similar to response to halothane

acidemia ( J:168222 )

• drop in blood pH during anesthesia is significantly greater than for controls

• blood lactate increase is significantly greater during anesthesia than for controls

hypercapnia ( J:168222 )

• pCO2 is significantly greater than for controls during anesthesia

abnormal calcium ion homeostasis ( J:168222 )

• calcium response of muscle cells to caffeine at lower caffeine concentrations (increased sensitivity)

• resting calcium ion concentration in myotubes is significantly higher than in controls

increased susceptibility to xenobiotic induced morbidity/mortality ( J:168222 )

• do not tolerate orbital blood collection well

• 50 % mortality during blood collection under halothane anesthesia

• hyperacute rigor mortis within 0.34 minutes of death, full body contracture

mortality/aging

increased susceptibility to xenobiotic induced morbidity/mortality ( J:168222 )

• do not tolerate orbital blood collection well

• 50 % mortality during blood collection under halothane anesthesia

• hyperacute rigor mortis within 0.34 minutes of death, full body contracture

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
malignant hyperthermia		DOID:8545	OMIM:PS145600	J:168222

Genotype
MGI:5314375

ht7

• Allelic Composition: Ryr1^tm1.1Inp/Ryr1⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

homeostasis/metabolism

increased core body temperature ( J:181523 )

• male mice exhibit increased basal core body temperature compared with wild-type mice

abnormal physiological response to xenobiotic ( J:181523 )

• prior to and after halothane treatment, myofibrils exhibit increased sex-dependent (greater in male mice) resting calcium concentration compared with wild-type cells

increased susceptibility to malignant hyperthermia ( J:181523 )

• 1 of 6 male mice treated with halothane develop fulminant malignant hyperthermia and dies unlike wild-type mice

• when bed temperature is equilibrated to 41C, all halothane-treated mice and some halothane-treated female mice develop fulminant malignant hyperthermia unlike wild-type mice

muscle

abnormal muscle physiology ( J:181523 )

• prior to and after halothane treatment, myofibrils exhibit increased sex-dependent (greater in male mice) resting calcium concentration compared with wild-type cells

Genotype
MGI:4881413

ht8

• Allelic Composition: Ryr1^tm1.1Dhm/Ryr1⁺
• Genetic Background: involves: 129S2/SvPasCrl * 129S6/SvEvTac

Kyphosis, hindlimb paresis and myofiber abnormalities in Ryr1^tm1.1Dhm/Ryr1⁺ mice

muscle

abnormal muscle fiber morphology ( J:155825 )

• myofibers undergo a transition from small, compacted areas resembling minicores in younger mice to nemaline-rod like inclusions in adults

• type 2 (fast) myofibers exhibit gross structural defects in myofibrillar organization; myofibrils vary greatly in thickness and there are numerous sites of splitting and thinning

• type 1 fiber hypotrophy/atrophy is detected in muscle fibers as early as 6 weeks of age

abnormal sarcomere morphology ( J:155825 )

• spatial disruption of sarcomeric and myofibrillar arrangement of myofibers due to minicore/core lesions

• type 2 myofibrils exhibit sarcomeric shortening, insertion of an additional sarcomere, and loss of sarcomeric register

abnormal Z line morphology ( J:155825 )

• core lesions show Z-line streaming and focal loss of a Z-disk

abnormal skeletal muscle fiber morphology ( J:155825 )

• skeletal muscle exhibits increased endomysial spacing and mild fibrosis

• mutant soleus fibers exhibit minicores (discrete foci of oxidative enzyme depletion) at 12 months of age; by 20 months of age, larger areas of oxidative enzyme depletion, consistent with cores, are seen in type 1 fibers

• intermyofibrillar spaces are reduced and mitochondria and sarcoplasmic reticulum are absent from core lesion areas

decreased skeletal muscle fiber diameter ( J:155825 )

• at 18 months of age, type I and type 2 fibers have reduced diameters, suggesting general fiber atrophy

increased variability of skeletal muscle fiber size ( J:155825 )

impaired muscle contractility ( J:155825 )

• fast-twitch and slow-twitch muscles exhibit a 28-34% lower force during a single twitch and submaximal titanic contractions at 2 months of age

• about 37% decrease in peak twitch force and maximal twitch rate of contraction in muscles

muscle weakness ( J:155825 )

• mobility impairment is first seen as weakness of hind limbs at around 6 months of age

myopathy ( J:155825 )

• heterozygotes exhibit slowly progressive congenital myopathy, however show no evidence of muscle wasting or skeletal muscle degeneration

respiratory system

respiratory distress ( J:155825 )

• mutants start to breathe regularly 15-20 min after birth compared to 5-7 min for wild-type mice

skeleton

kyphosis ( J:155825 )

• heterozygotes develop dorsal kyphosis in the cervicothoracic region with age, most likely due to overuse of the forelimbs for locomotion

growth/size/body

decreased body weight ( J:155825 )

• average body weight is about 15% lower than in wild-type

behavior/neurological

abnormal locomotor behavior ( J:155825 )

• 80% of heterozygotes show varying degrees of motor dysfunction by 10 months of age

hindlimb paralysis ( J:155825 )

• by 12 months of age, 14% of mutants exhibit complete hind limb paralysis

homeostasis/metabolism

cyanosis ( J:155825 )

• mutants are flaccid and cyanotic during the first minutes after delivery

adipose tissue

decreased total body fat amount ( J:155825 )

• very low fat deposits

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
congenital myopathy 1A		DOID:3529	OMIM:117000	J:155825

Genotype
MGI:3620044

ht9

• Allelic Composition: Ryr1^tm1Slh/Ryr1⁺
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

muscle

abnormal muscle physiology ( J:105738 )

• isolated muscle sarcoplasmic reticulum vesicles have a significant reduction in Ca2+ loading at 37 degrees C and voltage dependent Ca2+ release is shifted toward more negative voltages in isolate myotubes

abnormal muscle contractility ( J:105738 )

• the soleus muscle is more sensitive to caffeine-induced activation in an in vitro contracture test

• increasing the temperature to 41 degrees C for 15 min or less induces full body contractures with agonal breathing, rigid extremities, and arched backs

• isolated muscles display increased basal tension between 35-36 degrees C (43-44 degrees C for the diaphragm)

homeostasis/metabolism

increased circulating potassium level ( J:105738 )

• during heat induced contractures serum potassium and creatine kinase levels increase by 80% and 163% respectively compared to pre-heat challenge levels suggesting rhabdomyolysis has occurred, no such increase is seen in wild-type mice after heating

abnormal body temperature homeostasis ( J:105738 )

• after heat challenge (increased external temperature to 41 degrees C for less than 15 min) body temperature increases to 43.4 +/- 0.8 degrees C compared to 41.1 +/- 0.3 degrees C in wild-type mice

behavior/neurological

enhanced behavioral response to xenobiotic ( J:105738 )

• exposure to about 5.5 x 10^-5 ml/cm³ isoflurane induces a rapid onset of malignant hyperthermic response with full body contractures and increased core temperatures

• increasing the room temperature from less than 25 degrees C to 30 degrees C increases the penetrance of the malignant hyperthermic response

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
malignant hyperthermia		DOID:8545	OMIM:PS145600	J:105738

Genotype
MGI:7260233

ht10

• Allelic Composition: Ryr1^em1Tmur/Ryr1⁺
• Genetic Background: Not Specified

homeostasis/metabolism

abnormal body temperature homeostasis ( J:322211 )

• mice anesthetized using intravenous anesthetics and exposed to environmental heat stress (35 degrees Celsius) exhibit heat stroke and die

• pretreatment of mice exposed to environmental heat stress with Cpd1 slows the rate of temperature rise but maximum rectal temperature does not change and none of the mice survive 120 min of heat stress, although time to death is prolonged

• mice exposed to environmental heat stress and then treated with Cpd1 when rectal temperature reached 39 degrees Celsius rescues most mice from heat stroke at 10 mg/kg Cpd1 and partially rescues at 3 mg/kg; treatment with Cpd1 when temperature reached 38 degrees Celsius rescues most mice from heat stroke

increased physiological sensitivity to xenobiotic ( J:322211 )

• isolated single flexor digitorum brevis muscle cells treated with halothane up to 0.1% or with isoflurane show an increase in intracellular calcium concentration that is not seen in wild-type cells

• isolated soleus muscles exhibit dose-dependent contracture during exposure to caffeine compared to wild-type muscles which show minimal contracture

increased susceptibility to malignant hyperthermia ( J:322211 )

• nearly 80% of mice anesthetized by isoflurane rapidly increase their rectal temperature to over 40 degrees Celsius, exhibit muscle rigidity, and die within 90 minutes from start of exposure compared to wild-type mice which show no elevation in rectal temperature

• in the remaining 20% of mice, exposure to isoflurane causes an increase in rectal temperature but does not exceed 39 degrees Celsius

• more males (90%) succumb to isoflurane than females (65%)

• males pretreated with 10 mg/kg, but not 3 mg/kg, of Cpd1 sodium salt (a derivative of oxolinic acid that inhibits the RyR1 channel) before isoflurane challenge show prevention of rise in rectal temperature and all mice survive

• mice anesthetized with isoflurane and administered Cpd1 when rectal temperature reached 39 degrees Celsius show a decrease in body temperature and 60% of mice treated with 3mg/kg and 100% of mice treated with 10mg/kg of Cpd1 survive

muscle

abnormal muscle physiology ( J:322211 )

• isolated single flexor digitorum brevis muscle cells treated with halothane up to 0.1% or with isoflurane show an increase in intracellular calcium concentration that is not seen in wild-type cells

• pretreatment of flexor digitorum brevis muscle cells with a Cpd1 sodium salt (a derivative of oxolinic acid that inhibits the RyR1 channel) reduces resting intracellular calcium concentration and completely abolishes halothane-induced or isoflurane-induced increases in intracellular calcium

• isolated soleus muscles exhibit dose-dependent contracture during exposure to caffeine compared to wild-type muscles which show minimal contracture

• pretreatment with Cpd1 decreases caffeine-induced contracture tension of soleus muscle basal tension of soleus muscle at 42 degrees Celsius is increased compared to in wild-type muscle and pre-treatment with Cpd1 reduces the heat-induced contracture

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
malignant hyperthermia		DOID:8545	OMIM:PS145600	J:322211