All Phenotypes Gfpt1<tm1c(EUCOMM)Wtsi> MGI Mouse

decreased grip strength ( J:265013 )

• starting at 6 weeks of age, mice show a significant reduction in the latency to fall from a wire grid at various time points up to 6 months of age in the inverted screen test assay

• however, the deficit in motor performance is not progressive over the first 6 months

muscle phenotype ( J:265013 )

N	• no pathological changes are observed in cardiac muscle

abnormal sarcolemma morphology ( J:265013 )

• EM revealed the presence of ectopic subsarcolemmal caveolae-like vesicular structures in intercostal muscle, indicating ER-Golgi-stress

abnormal sarcoplasmic reticulum morphology ( J:265013 )

• soleus and tibialis anterior (TA) muscles show significantly larger sarcoplasmic caveolin-3 positive punctae than control muscles

abnormal skeletal muscle fiber morphology ( J:265013 )

• skeletal muscles show occasional rounded myofibers, a small number of fibers with internal nuclei, necrotic fibers, and presence of atrophic and hypertrophic myofibers, some of which exhibit splitting

• tubular aggregates are detected in some myofibers in all muscles examined along with the replacement of myofibers with adipose tissue, esp. in diaphragm muscle

• no differences in the fiber type proportion are observed in the soleus or TA muscles

• no tubular aggregate fiber type specific predominance is observed in the soleus or TA muscles

skeletal muscle fiber necrosis ( J:265013 )

• necrotic skeletal myofibers are observed

decreased skeletal muscle fiber size ( J:265013 )

• the intercostal and soleus muscles exhibit a shift towards smaller fibers (29% and 26%, respectively) relative to control muscles

skeletal muscle fiber atrophy ( J:265013 )

• at 3 months of age, the diaphragm muscle shows muscle fiber atrophy along with a progressive replacement of muscle tissue by fibroadipose tissue

increased skeletal muscle fiber size ( J:265013 )

• skeletal muscle fiber hypertrophy is observed; the EDL muscle exhibits a shift towards larger fibers (18%) relative to control muscle

increased variability of skeletal muscle fiber size ( J:265013 )

• differences in fiber size are greatest in EDL muscle (61%), followed by the soleus (56%), intercostal (29%) and TA (26%) muscles

• however, median cross-sectional area (CSA) values for TA muscle fiber size remain normal

centrally nucleated skeletal muscle fibers ( J:265013 )

• a small number of skeletal myofibers have centrally located nuclei

impaired skeletal muscle contractility ( J:265013 )

• at 3 months of age, the maximal isometric tetanic force in diaphragm muscle at 150 Hz is reduced by 35.3% relative to that in control mice

abnormal muscle electrophysiology ( J:265013 )

• at 3 months of age, a progressive decline in force generated by the TA muscle is evident from 80 tetanic nerve stimulations of the common peroneal nerve (CPN) at 120 Hz (80, 42.9%; 90, 47.7%; 100, 64.7%), whereas a significant (26.1%) reduction of force in control mice is only seen after 100 stimulations compared with baseline

• a progressive reduction in force generated by the diaphragm muscle is noted between 50 and 100 tetanic nerve stimulations at 150 Hz

increased muscle fatigability ( J:265013 )

• at 3 months of age, mice show a progressive increase in TA muscle fatigability, expressed as the % decrease of baseline force, after 80 (20.8%), 90 (26.4%) and 100 (38.7%) tetanic nerve stimulations at 120 Hz relative to control mice

• a progressive increase in diaphragm muscle fatigability is noted between 50 and 100 tetanic nerve stimulations at 150 Hz

muscle weakness ( J:265013 )

• mice exhibit muscle weakness as early as 6 weeks of age

myopathy ( J:265013 )

• mice develop progressive myopathic changes in TA, intercostal, soleus, extensor digitorum longus (EDL) and diaphragm muscles

abnormal myelin sheath morphology ( J:265013 )

• presynaptic alterations in intercostal muscle NMJs include irregular and occasionally convoluted presynaptic myelin sheaths

decreased myelin sheath thickness ( J:265013 )

• the diameter of myelin sheaths is significantly reduced in intercostal muscle

abnormal neuromuscular synapse morphology ( J:265013 )

• at 3 months of age, acetylcholine receptor (AChR) clusters in TA, intercostal, soleus and EDL muscles appear smaller and fragmented relative to those in control muscles

• reduction in AChR cluster area is greatest in the TA (45%), followed by the EDL (33%), soleus (28%) and intercostal (27%) muscles

• mean number of fragments/AChR cluster is greatest in the soleus, followed by the EDL, intercostal and TA muscles

• presynaptic changes include discontinuous and disorganized axonal projections, thinner irregular myelin sheaths and remodeling of motor nerve terminals; however, axons can project normally to endplates with no signs of overshooting, retractions or axonal sprouting

• NMJs in intercostal muscle exhibit fewer postsynaptic junctional folds, accumulation of tubular aggregates and subsarcolemmal vesicular structures, deposits of dense filamentous-like material, irregular and convoluted presynaptic myelin sheaths, and a reduction in the diameter of myelin sheaths

• AChR turnover rate in TA muscles is normal

growth/size/body region phenotype ( J:265013 )

N	• although mice are slightly smaller than control mice, no significant differences in body weight are observed over the first 6 months

skeletal muscle fiber necrosis ( J:265013 )

• necrotic skeletal myofibers are observed

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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
congenital myasthenic syndrome 12		DOID:0110660	OMIM:610542	J:265013

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