Phenotypes associated with this allele

• Allele Symbol: Cacna1s^mdg
• Allele Name: muscular dysgenesis
• Allele ID: MGI:1856326
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cacna1s^mdg/Cacna1s^mdg	involves: 129P1/ReJ * STOCK T/t^4	MGI:2672097
hm2	Cacna1s^mdg/Cacna1s^mdg	involves: 129 * STOCK T/t^4	MGI:3722785
hm3	Cacna1s^mdg/Cacna1s^mdg	involves: STOCK T/t^4	MGI:2658922

Genotype
MGI:2672097

hm1

• Allelic Composition: Cacna1s^mdg/Cacna1s^mdg
• Genetic Background: involves: 129P1/ReJ * STOCK T/t⁴

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

homeostasis/metabolism

abnormal enzyme/coenzyme activity ( J:6592 , J:34235 )

• acetylcholinesterase mRNAs and activity is reduced in skeletal, but not cardiac, muscle (J:34235)

muscle

abnormal muscle morphology ( J:6592 )

• focal accumulation of acetycholinesterase on most of the surface of muscle masses

abnormal diaphragm morphology ( J:6592 )

• diaphragm muscle fibers show a higher degree of maturity than controls

impaired skeletal muscle contractility ( J:5371 )

• skeletal muscle fibers grown in culture do not contract, however, they display normal passive and active membrane potentials and acetlylcholine sensitivity

nervous system

abnormal innervation pattern to muscle ( J:6592 )

• extension of the zone of innervation to most muscle, with increased axonal sprouting

• often seen double innervation on the same site and more frequently, on single axon that runs for long distances along muscle fiber and possesses regularly interspaced varicositites

• before entering the muscle, the impregnated nerves sometimes show localized swellings

Genotype
MGI:3722785

hm2

• Allelic Composition: Cacna1s^mdg/Cacna1s^mdg
• Genetic Background: involves: 129 * STOCK T/t⁴

muscle

abnormal muscle development ( J:15029 )

• myoblast fusion occurs earlier (by about 12 hours) and is more extensive in mutant cultures than in wild-type

impaired muscle contractility ( J:7390 , J:15029 )

• although mutant myotubes do not contract when grown in culture, they become contractile when co-cultured with normal nerve cord, an effect due to formation of normal muscle-nerve synapses (J:7390)

Genotype
MGI:2658922

hm3

• Allelic Composition: Cacna1s^mdg/Cacna1s^mdg
• Genetic Background: involves: STOCK T/t⁴

mortality/aging

perinatal lethality, complete penetrance ( J:4466 )

• perinatal death most likely due to poorly developed musculature of the thorax and diaphragm and inability to breathe

muscle

abnormal tongue muscle morphology ( J:14970 )

• disorganization of the tongue is apparent at E15.5 and in newborns is abnormal

abnormal muscle development ( J:5576 , J:14970 )

• myotube formation in culture is more extensive than in wild-type controls, however as in wild-type, myogenesis occurs through cell fusion and not by abnormal mitotic or amitotic divisions (J:5576)

• skeletal myoblasts fail to differentiate into striated myotubes (J:14970)

abnormal muscle fiber morphology ( J:7295 , J:7296 )

• isolated myofibers have multiple acetylcholine receptor clusters, larger clusters of more variable morphology, variable receptor density, and higher levels of extrajunctional receptors (J:7295)

• newly formed myotubes lack the basal lamina at E14, however biosynthesis of the basal lamina is not totally defective as, at E18, myotubes have basal lamina sheaths (J:7296)

• majority of muscle fibers at E18-19 are thinner, contain fewer cross striations than normal and contain from 1-4 accumulations of high acetylcholinesterase activity (J:7296)

abnormal sarcomere morphology ( J:18533 )

• sacromeres are never fully organized in skeletal myotubes grown in culture

abnormal Z line morphology ( J:5283 , J:18533 )

• Z bands of skeletal muscle are irregular in outline, indistinct, or wider than in controls (J:5283)

dilated sarcoplasmic reticulum ( J:5283 )

• sarcoplasmic reticulum appears dilated beginning at E14

abnormal skeletal muscle fiber morphology ( J:4724 , J:5283 , J:18533 )

• primary myotube numbers are depressed by 20-30% (J:4724)

• number of secondary myotubes in EDL muscles at E15 is more than double that in controls (J:4724)

• skeletal abnormalities between E14-19 include retraction clots in myotubes, nuclear inclusions, nuclear encircling, pycnotic nuclei, increased cellular death, dilated sarcoplasmic reticulum, swollen mitochondria and fibril and filament disarrangement and degeneration (J:5283)

abnormal diaphragm morphology ( J:7295 , J:7296 )

• muscle mass of the diaphragm is 60% of normal (J:7295)

• distribution of high acetylcholine receptor density patches is aberrantly scattered beyond the normal innervation pattern in diaphragms (J:7295)

• higher total level of toxin binding sites per diaphragm (J:7295)

thin diaphragm muscle ( J:4466 )

• diaphragm is very thin

decreased skeletal muscle mass ( J:14970 )

absent skeletal muscle ( J:4466 )

muscle degeneration ( J:14970 )

• abnormal differentiation and subsequent degeneration of embryonic skeletal muscle cells, beginning at E13.25

• however, cardiac and smooth muscle are normal

abnormal muscle physiology ( J:641 )

• T-type current density in myotubes is about 40-60% of normal throughout the prenatal period studied

• the high threshold sustained current (L-type current) density that increases gradually with age in wild-type myotubes is absent in homozygotes

impaired skeletal muscle contractility ( J:4724 , J:18533 )

• absence of excitation-contraction coupling (J:4724)

• myotubes in primary culture never contract spontaneously or in response to electrical stimulation (J:18533)

• microinjection of a Cacna1s cDNA into mutant myotubes restores excitation-contraction coupling (J:18533)

craniofacial

enlarged interparietal bone ( J:4466 )

• slight enlargement of the interparietal bone

enlarged occipital bone ( J:4466 )

• slight enlargement of the occipital bone

abnormal mandible morphology ( J:4466 )

• mandible has an abnormally pronounced curvature and the proximal structures are smaller

small mandibular condyloid process ( J:4466 )

• smaller condyloid process

small mandibular coronoid process ( J:4466 )

• smaller coronoid process

short mandible ( J:4466 , J:14970 )

• mandible is reduced in length (J:4466)

• mutants with cleft palate have mandibles that are even shorter than mutants without cleft palate (J:4466)

micrognathia ( J:4466 )

• 100% penetrance

cleft secondary palate ( J:4466 )

• 77% of newborns have a cleft palate; the tongue remains lodged between the lateral palatine processes in these mutants

abnormal tongue morphology ( J:4466 )

• softer tongue

abnormal tongue muscle morphology ( J:14970 )

• disorganization of the tongue is apparent at E15.5 and in newborns is abnormal

decreased tongue size ( J:4466 )

shortened head ( J:4466 )

• head is slightly shortened, however individual skull bones are normal in shape

homeostasis/metabolism

edema ( J:4466 , J:14970 )

• the liver and kidneys appear slightly edematous in some mutants (J:4466)

• fetuses show severe and generalized edema at E13.25-E13.5, especially dorsally, however by E18.5, edema subsides and is less severe (J:14970)

extremity edema ( J:4466 , J:14970 )

• limb edema predominates at E17.5-E18.5 (J:14970)

skeleton

absent deltoid tuberosity ( J:4466 )

small clavicle ( J:4466 )

• clavicle is shorter with a narrower sternal end

decreased diameter of long bones ( J:4466 )

• long bones of the limbs are thinner, especially at the ends of the diaphysis

small scapula ( J:4466 )

abnormal axial skeleton morphology ( J:4466 )

enlarged interparietal bone ( J:4466 )

• slight enlargement of the interparietal bone

enlarged occipital bone ( J:4466 )

• slight enlargement of the occipital bone

abnormal mandible morphology ( J:4466 )

• mandible has an abnormally pronounced curvature and the proximal structures are smaller

small mandibular condyloid process ( J:4466 )

• smaller condyloid process

small mandibular coronoid process ( J:4466 )

• smaller coronoid process

short mandible ( J:4466 , J:14970 )

• mandible is reduced in length (J:4466)

• mutants with cleft palate have mandibles that are even shorter than mutants without cleft palate (J:4466)

micrognathia ( J:4466 )

• 100% penetrance

abnormal sternum morphology ( J:4466 , J:14970 )

• slight delay in fusion of sternal primorida is noticeable at E14.5 (J:14970)

abnormal sternebra morphology ( J:4466 )

• sternebrae are usually fused and/or duplicated

sternebra fusion ( J:4466 )

• usual

short sternum ( J:4466 )

abnormal rib morphology ( J:4466 , J:14970 )

• ribs extend perpendicularly from the vertebral column (J:4466)

long ribs ( J:4466 )

• the 7th-13th ribs are longer

thin ribs ( J:4466 )

abnormal vertebral column morphology ( J:4466 )

thoracic vertebral fusion ( J:4466 )

• 40% exhibit fusion of the cervical and thoracic vertebrae; all fusions of thoracic vertebrae occur between 4th and 7th vertebrae

abnormal spine curvature ( J:14970 )

• dorsal curvature is seen at E14.5 when the spine begins to straighten in wild-type

kyphosis ( J:4466 )

• kyphosis in the cervical region of the vertebral column

abnormal cervical vertebrae morphology ( J:4466 )

• cervical vertebrae are abnormally broad and closely adjacent to each other

cervical vertebral fusion ( J:4466 )

• 40% exhibit fusion of the cervical and thoracic vertebrae

abnormal cartilage morphology ( J:4466 )

• sternum and ribs show abnormalities of their cartilaginous portions; the cartilage primordia, especially anteriorly, are smaller and not fused

abnormal joint morphology ( J:14970 )

• development of joint cavities between limb and girdle primordia is abnormal, with no joint cavities seen at E16.5

digestive/alimentary system

cleft secondary palate ( J:4466 )

• 77% of newborns have a cleft palate; the tongue remains lodged between the lateral palatine processes in these mutants

abnormal tongue morphology ( J:4466 )

• softer tongue

abnormal tongue muscle morphology ( J:14970 )

• disorganization of the tongue is apparent at E15.5 and in newborns is abnormal

decreased tongue size ( J:4466 )

behavior/neurological

limb grasping ( J:4466 )

• limbs are held in a typical clasping position

no spontaneous movement ( J:14970 )

• no spontaneous movement is observed at E15.5 and no motor response to tactile and electrical stimuli is seen at E16.5

growth/size/body

cleft secondary palate ( J:4466 )

• 77% of newborns have a cleft palate; the tongue remains lodged between the lateral palatine processes in these mutants

abnormal tongue morphology ( J:4466 )

• softer tongue

abnormal tongue muscle morphology ( J:14970 )

• disorganization of the tongue is apparent at E15.5 and in newborns is abnormal

decreased tongue size ( J:4466 )

shortened head ( J:4466 )

• head is slightly shortened, however individual skull bones are normal in shape

abnormal thoracic cavity morphology ( J:4466 )

• thoracic cavity is wider and shorter

abnormal fetal size ( J:14970 )

• mutants at E16.5 appear broader dorsoventrally than normal

limbs/digits/tail

absent deltoid tuberosity ( J:4466 )

adipose tissue

increased brown adipose tissue amount ( J:14970 )

• brown adipose tissue becomes hyperplastic by E16.5 and fat bodies do not show as much lobulation as wild-type and appear larger and denser

nervous system

abnormal innervation pattern to muscle ( J:7295 )

• innervation of the diaphragm is abnormal by E16, with extensive overgrowth and generalized sprouting of nerve endings

abnormal dorsal root ganglion morphology ( J:14970 )

• some indication of occasional degeneration of spinal ganglia neurons at late stages of gestation, however most neurons appear normal

abnormal phrenic nerve morphology ( J:7296 )

• extensive branching of the phrenic nerve at E13.5 compared to the simple pattern of a few secondary trunks in wild-type diaphragm

• the phrenic nerve and its primary and secondary branches display a higher acetylcholinesterase cytochemical activity than in wild-type

abnormal spinal cord ventral horn morphology ( J:14970 )

• some indication of occasional degeneration of anterior horn motor neurons at late stages of gestation, however most neurons appear normal

integument

loose skin ( J:4466 )

• skin is loose and smooth and appears to lack normal adherence to underlying tissues