Phenotypes Associated with This Genotype

Genotype
MGI:3033756

• Allelic Composition: Gaa^tm1Rabn/Gaa^tm1Rabn
• Genetic Background: involves: 129X1/SvJ * C57BL/6

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

Abnormal lysosomal glycogen storage in heart and skeletal muscle of Gaa^tm1Rabn/Gaa^tm1Rabn mice

behavior/neurological

impaired coordination ( J:76435 )

• severely impaired on a rotarod at 8-11 months of age

decreased grip strength ( J:48839 )

• in the wire-hang task, homozygous mutants perform poorly, indicating poor muscular function and grip strength

• at 15-16 weeks of age, homozygous mutant mice are almost never able to hold on to the inverted screen for more than 2 minutes

abnormal gait ( J:48839 , J:76435 )

• at 7-9 months of age, mice display a weak, waddling gait (J:48839)

decreased vertical activity ( J:48839 )

• starting at 3.5 weeks of age, display a striking reduction in vertical activity in the open field

decreased locomotor activity ( J:48839 , J:76435 )

• as early as 3.5 weeks of age, display reduced activity in the horizontal open field test, and consistently perform significantly worse than age-matched heterozygotes when placed in an open field environment (J:48839)

• develop abnormal field behavior within the first months of life (J:76435)

hindlimb paralysis ( J:76435 )

• by 16-18 months of age, display near paralysis of the hindlimbs and an abnormal footprint pathway

liver/biliary system

increased liver glycogen level ( J:235790 )

♂ • after overnight fasting, 3-month-old male mice show high levels of lysosomal glycogen storage in liver tissue, consistent with strong PAS+ glycogen staining

♂ • however, at 3 months of age, fed liver glycogen levels are not significantly different from those in wild-type controls

nervous system

increased brain glycogen level ( J:76435 )

• massive accumulation of glycogen in brain

muscle

increased cardiac muscle glycogen level ( J:48839 , J:76435 , J:235790 )

• accumulation of lysosomal glycogen in the heart (J:48839)

• massive accumulation of glycogen in heart (J:76435)

♂ • after overnight fasting, 3-month-old male mice show high levels of lysosomal glycogen storage in heart muscle tissue (J:235790)

cardiomyopathy ( J:48839 , J:76435 )

increased skeletal muscle glycogen level ( J:48839 , J:73924 , J:235790 )

• accumulation of lysosomal glycogen in skeletal muscle (J:48839)

• in contrast to frozen quadricep muscles from wild-type mice which contain very little glycogen and >50% of their glycogen phosphorylase is in the form of phosphorylase-a (Ph-a), quadricep muscles from homozygous mutant mice have little or no Ph-a activity and contain 20 times or more glycogen (J:73924)

♂ • after overnight fasting, 3-month-old male mice show high levels of lysosomal glycogen storage in skeletal muscle tissue (J:235790)

abnormal muscle fiber morphology ( J:48839 )

• display a significant reduction in the number of myofibrils and lack of lateral myofibrillar registration

abnormal sarcomere morphology ( J:48839 )

• signs of sarcomere degradation

abnormal Z line morphology ( J:48839 )

• deformation of Z lines

muscle weakness ( J:48839 )

• seen in older mice (8-9 months)

progressive muscle weakness ( J:48839 , J:76435 )

• at 7-9 months of age, homozygotes show obvious signs of muscle weakness and muscle wasting (J:48839)

• by 16-18 months, homozygotes exhibit a severe lower back muscle wasting and anterior muscle wasting (J:48839)

myopathy ( J:76435 )

• develop a progressive muscle wasting disorder with clinical features of glycogen storage disease II; average age of onset is 7.1 months for females and 8.1 months for males

cardiovascular system

increased cardiac muscle glycogen level ( J:48839 , J:76435 , J:235790 )

• accumulation of lysosomal glycogen in the heart (J:48839)

• massive accumulation of glycogen in heart (J:76435)

♂ • after overnight fasting, 3-month-old male mice show high levels of lysosomal glycogen storage in heart muscle tissue (J:235790)

cardiomyopathy ( J:48839 , J:76435 )

cellular

abnormal lysosome morphology ( J:48839 )

• at >3 weeks of age, cardiac and skeletal muscle lysosomes increase in size and number, and display increased density of accumulated glycogen particles

• at >3 weeks of age, some cardiac and skeletal muscle lysosomes appear broken, suggesting that leakage of lysosomal proteases may contribute to the damage of muscle structure

homeostasis/metabolism

increased cardiac muscle glycogen level ( J:48839 , J:76435 , J:235790 )

• accumulation of lysosomal glycogen in the heart (J:48839)

• massive accumulation of glycogen in heart (J:76435)

♂ • after overnight fasting, 3-month-old male mice show high levels of lysosomal glycogen storage in heart muscle tissue (J:235790)

increased brain glycogen level ( J:76435 )

• massive accumulation of glycogen in brain

increased liver glycogen level ( J:235790 )

♂ • after overnight fasting, 3-month-old male mice show high levels of lysosomal glycogen storage in liver tissue, consistent with strong PAS+ glycogen staining

♂ • however, at 3 months of age, fed liver glycogen levels are not significantly different from those in wild-type controls

increased skeletal muscle glycogen level ( J:48839 , J:73924 , J:235790 )

• accumulation of lysosomal glycogen in skeletal muscle (J:48839)

• in contrast to frozen quadricep muscles from wild-type mice which contain very little glycogen and >50% of their glycogen phosphorylase is in the form of phosphorylase-a (Ph-a), quadricep muscles from homozygous mutant mice have little or no Ph-a activity and contain 20 times or more glycogen (J:73924)

♂ • after overnight fasting, 3-month-old male mice show high levels of lysosomal glycogen storage in skeletal muscle tissue (J:235790)

skeleton

kyphosis ( J:76435 )

• by 16-18 months, homozygous mutant mice exhibit a striking kyphosis

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
glycogen storage disease II		DOID:2752	OMIM:232300	J:48839 , J:76435