Phenotypes associated with this allele

• Allele Symbol: Ryr1^tm1.1Dhm
• Allele Name: targeted mutation 1.1, David H MacLennan
• Allele ID: MGI:4418317
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Ryr1^tm1.1Dhm/Ryr1^tm1.1Dhm	involves: 129S6/SvEvTac * 129X1/SvJ	MGI:4418335
ht2	Ryr1^tm1.1Dhm/Ryr1^+	involves: 129S2/SvPasCrl * 129S6/SvEvTac	MGI:4881413

Genotype
MGI:4418335

hm1

• Allelic Composition: Ryr1^tm1.1Dhm/Ryr1^tm1.1Dhm
• Genetic Background: involves: 129S6/SvEvTac * 129X1/SvJ

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

Small size, abnormal posture, reduced skeletal muscle bulk, myotube abnormalities, and underdeveloped dermis in Ryr1^tm1.1Dhm/Ryr1^tm1.1Dhm neonates

mortality/aging

neonatal lethality, complete penetrance ( J:127629 )

• mice die shortly after birth likely due to asphyxia

muscle

abnormal muscle development ( J:127629 )

• neonates myotubes are scarce and poorly aligned with no cross striation embedded in an amorphous mass of connective tissue unlike in wild-type mice

• myotubes fail to form myofibers unlike in wild-type mice

• myogenesis arrest at a stage where the nuclei is centrally located

abnormal diaphragm morphology ( J:127629 )

• the diaphragm is transparent unlike in wild-type mice

decreased skeletal muscle mass ( J:127629 )

• in neonates

skeletal muscle degeneration ( J:127629 )

• likely from E15.5

abnormal muscle physiology ( J:127629 )

• ligand-induced and dihydropyridine receptor-activated calcium ion release is absent unlike in wild-type myotubes

impaired skeletal muscle contractility ( J:127629 )

• neonates lack skeletal muscle contractions unlike wild-type mice

skeleton

domed cranium ( J:127629 )

abnormal thoracic cage shape ( J:127629 )

• slightly excavated and laterally enlarged

kyphosis ( J:127629 )

• persistent cervical kyphosis

delayed bone ossification ( J:127629 )

• especially in the cranial part of the skull, heel bones, and phalanges of the digits

cardiovascular system

abnormal coronary artery morphology ( J:127629 )

• secondary blood vessels branching from the coronary artery are poorly developed or absent compared to in wild-type mice

delayed heart development ( J:127629 )

• cardiac development is delayed with hearts retaining an antero-posterior orientation and visible interventricular groove unlike in wild-type mice

• the size, shape, and wall thickness of the right and left ventricles remains equal unlike in wild-type mice

ostium primum atrial septal defect ( J:127629 )

• underdeveloped septum primum

ostium secundum atrial septal defect ( J:127629 )

• poorly developed or absent septum secundum

abnormal interventricular groove morphology ( J:127629 )

• mice retain the interventricular groove unlike wild-type mice

behavior/neurological

unresponsive to tactile stimuli ( J:127629 )

• in neonates

abnormal posture ( J:127629 )

• neonates have a curved position unlike wild-type mice

paralysis ( J:127629 )

• neonates lack skeletal muscle contractions unlike wild-type mice

growth/size/body

cleft secondary palate ( J:127629 )

• 80% of mice exhibit a cleft secondary palate

decreased birth body size ( J:127629 )

decreased birth weight ( J:127629 )

fetal growth retardation ( J:127629 )

• at E15

adipose tissue

increased brown adipose tissue amount ( J:127629 )

• in the cervical region

craniofacial

domed cranium ( J:127629 )

cleft secondary palate ( J:127629 )

• 80% of mice exhibit a cleft secondary palate

homeostasis/metabolism

cyanosis ( J:127629 )

• shortly after birth

skin edema ( J:127629 )

• mild and local at E13.5 to E14.5 but recedes by E16.5

digestive/alimentary system

cleft secondary palate ( J:127629 )

• 80% of mice exhibit a cleft secondary palate

integument

underdeveloped hair follicles ( J:127629 )

abnormal dermal layer morphology ( J:127629 )

• the dermis is underdeveloped compared to in wild-type mice

tight skin ( J:127629 )

translucent skin ( J:127629 )

abnormal skin condition ( J:127629 )

• skin is smooth, transparent, and tight unlike in wild-type mice

skin edema ( J:127629 )

• mild and local at E13.5 to E14.5 but recedes by E16.5

Genotype
MGI:4881413

ht2

• 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