Phenotypes associated with this allele

• Allele Symbol: Gaa^tm1Rabn
• Allele Name: targeted mutation 1, Nina Raben
• Allele ID: MGI:2148550
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Gaa^tm1Rabn/Gaa^tm1Rabn	involves: 129X1/SvJ * C57BL/6	MGI:3033756
cx2	Gaa^tm1Rabn/Gaa^tm1Rabn Tg(CMV-GAA*P545L)#Kjv/0	involves: 129X1/SvJ * C57BL/6	MGI:5620663
cx3	Gaa^tm1Rabn/Gaa^tm1Rabn Stbd1^tm1Bsn/Stbd1^tm1Bsn	involves: 129X1/SvJ * C57BL/6	MGI:6780079

Genotype
MGI:3033756

hm1

• 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

Genotype
MGI:5620663

cx2

• Allelic Composition: Gaa^tm1Rabn/Gaa^tm1Rabn; Tg(CMV-GAA*P545L)#Kjv/0
• Genetic Background: involves: 129X1/SvJ * C57BL/6

cellular

abnormal lysosome physiology ( J:219022 )

• mice exhibit lysosomal proliferation indicating increased lysosomal content in the heart and skeletal muscle

homeostasis/metabolism

increased glycogen level ( J:219022 )

• glycogen levels in the heart and gastrocnemius muscle are elevated 4- and 3.5-fold, respectively, compared to wild-type mice and are about 40% and 53%, respectively of those in single Gaa homozygotes

• treatment with AT2220 (1-deoxynojirimycin hydrochloride; duvoglustat hydrochloride) reduces glycogen levels

increased skeletal muscle glycogen level ( J:219022 )

muscle

increased skeletal muscle glycogen level ( J:219022 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
glycogen storage disease II		DOID:2752	OMIM:232300	J:219022

Genotype
MGI:6780079

cx3

• Allelic Composition: Gaa^tm1Rabn/Gaa^tm1Rabn; Stbd1^tm1Bsn/Stbd1^tm1Bsn
• Genetic Background: involves: 129X1/SvJ * C57BL/6

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:235790 )

♂N • after overnight fasting, double mutant mice show normal protein expression of two key enzymes for glycogen synthesis (GYS2 and GBE1) in liver, indicating normal glycogen synthesis

♂N • after overnight fasting, increase in LC3-II in the liver of double mutant mice is similar to that in single Gaa^tm1Rabn homozygotes, indicating normal autophagy activation

increased cardiac muscle glycogen level ( J:235790 )

♂ • after overnight fasting, 3-month-old double mutant male mice show significantly higher heart muscle glycogen levels than wild-type controls or single Stbd1^tm1Bsn homozygotes; however, glycogen contents in heart muscle are not significantly different from those in single Gaa^tm1Rabn homozygotes

increased liver glycogen level ( J:235790 )

♂ • after overnight fasting, 3-month-old double mutant male mice show significantly higher liver glycogen levels than wild-type controls or single Stbd1^tm1Bsn homozygotes; however, liver glycogen content is only 27% of that in single Gaa^tm1Rabn homozygotes, consistent with a marked reduction in PAS+ glycogen staining

♂ • at 13 months of age, fasting liver glycogen content in double mutant mice is significantly higher than that at 3 months of age, but only 40% of that in 13-month-old single Gaa^tm1Rabn homozygotes

♂ • exogenous expression of human STBD1 in double mutant mice restores the liver lysosomal glycogen content to the level of single Gaa^tm1Rabn homozygotes

♂ • at 3 months of age, fed liver glycogen levels in double mutant mice are similar to those in wild-type controls and single Gaa^tm1Rabn homozygotes

increased skeletal muscle glycogen level ( J:235790 )

♂ • after overnight fasting, 3-month-old double mutant male mice show significantly higher skeletal muscle glycogen levels than wild-type controls or single Stbd1^tm1Bsn homozygotes; however, glycogen contents in skeletal muscle are not significantly different from those in single Gaa^tm1Rabn homozygotes

liver/biliary system

increased liver glycogen level ( J:235790 )

♂ • after overnight fasting, 3-month-old double mutant male mice show significantly higher liver glycogen levels than wild-type controls or single Stbd1^tm1Bsn homozygotes; however, liver glycogen content is only 27% of that in single Gaa^tm1Rabn homozygotes, consistent with a marked reduction in PAS+ glycogen staining

♂ • at 13 months of age, fasting liver glycogen content in double mutant mice is significantly higher than that at 3 months of age, but only 40% of that in 13-month-old single Gaa^tm1Rabn homozygotes

♂ • exogenous expression of human STBD1 in double mutant mice restores the liver lysosomal glycogen content to the level of single Gaa^tm1Rabn homozygotes

♂ • at 3 months of age, fed liver glycogen levels in double mutant mice are similar to those in wild-type controls and single Gaa^tm1Rabn homozygotes

cardiovascular system

increased cardiac muscle glycogen level ( J:235790 )

♂ • after overnight fasting, 3-month-old double mutant male mice show significantly higher heart muscle glycogen levels than wild-type controls or single Stbd1^tm1Bsn homozygotes; however, glycogen contents in heart muscle are not significantly different from those in single Gaa^tm1Rabn homozygotes

muscle

increased cardiac muscle glycogen level ( J:235790 )

♂ • after overnight fasting, 3-month-old double mutant male mice show significantly higher heart muscle glycogen levels than wild-type controls or single Stbd1^tm1Bsn homozygotes; however, glycogen contents in heart muscle are not significantly different from those in single Gaa^tm1Rabn homozygotes

increased skeletal muscle glycogen level ( J:235790 )

♂ • after overnight fasting, 3-month-old double mutant male mice show significantly higher skeletal muscle glycogen levels than wild-type controls or single Stbd1^tm1Bsn homozygotes; however, glycogen contents in skeletal muscle are not significantly different from those in single Gaa^tm1Rabn homozygotes