Phenotypes Associated with This Genotype

Genotype
MGI:6273835

• Allelic Composition: Gyg1^{tm1a(KOMP)Wtsi}/Gyg1^{tm1a(KOMP)Wtsi}
• Genetic Background: involves: C57BL/6N
• Cell Lines: EPD0124_3_C03

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

mortality/aging

neonatal lethality, incomplete penetrance ( J:244440 , J:300001 )

• although present at normal Mendelian ratios at E18.5, most homozygotes die shortly after birth due to cardiorespiratory failure (J:244440)

• only 4% of homozygotes are obtained from heterozygous matings at 2 weeks of age (J:244440)

• pups show 90% mortality due to respiratory failure; the 10% of pups that survive thrive and reach a regular life span (J:300001)

muscle

increased cardiac muscle glycogen level ( J:244440 )

• at 15-20 weeks of age, male mice show a 7-fold increase of glycogen levels in cardiac muscle relative to wild-type controls

increased skeletal muscle glycogen level ( J:244440 )

• at 15-20 weeks of age, male mice show a 4-fold increase of glycogen levels in skeletal muscle relative to wild-type controls

• glycogen granules isolated from skeletal muscle are larger and extend over a wide range of sizes, with up to a 4-fold greater radius than that in wild-type controls

• EM revealed accumulation of large glycogen particles in the intermyofibrillar space of skeletal (quadriceps) muscle

• both soleus and EDL muscles show increased glycogen levels relative to wild-type muscles, with no significant difference in muscle weights

• however, no changes in the proportion of fiber types are observed in soleus and EDL muscles

abnormal muscle electrophysiology ( J:244440 )

• slow-twitch soleus muscle generates a ~2-fold greater isometric force than its wild-type control at all stimulation frequencies tested, suggesting a switch of the oxidative soleus toward a more glycolytic type

• in contrast, fast-twitch EDL muscle generates a force similar to that of wild-type controls

homeostasis/metabolism

impaired exercise endurance ( J:244440 )

• in spite of increased skeletal muscle glycogen level, mice reach exhaustion earlier than wild-type controls in a treadmill endurance test

decreased aerobic running capacity ( J:244440 )

• mice cover a shorter distance than wild-type controls in a treadmill endurance test

abnormal lipid oxidation ( J:244440 )

• adult mice show decreased lipid oxidation esp. during the light phase

decreased energy expenditure ( J:244440 )

• adult mice show decreased energy expenditure both during the light and dark phase

• however, body weight, fat:lean body mass, food intake and locomotor activity are normal

decreased carbon dioxide production ( J:244440 )

• adult mice show lower carbon dioxide production both during the light and dark phase

decreased oxygen consumption ( J:244440 )

• adult mice show lower oxygen consumption both during the light and dark phase

• however, the respiratory exchange ratio (RER) is normal

abnormal glucose homeostasis ( J:244440 )

• adult mice show decreased glucose oxidation esp. during the dark phase

abnormal glycogen homeostasis ( J:244440 )

• unexpectedly, mice are able to synthesize glycogen, as shown by normal glycogen levels in liver and brain relative to wild-type controls

• mass spectrometry-based analysis showed that glycogen is synthesized without a protein primer

• however, glycogen accumulation does not increase progressively with age in any tissue (liver, brain, skeletal or cardiac muscle)

increased cardiac muscle glycogen level ( J:244440 )

• at 15-20 weeks of age, male mice show a 7-fold increase of glycogen levels in cardiac muscle relative to wild-type controls

decreased lung glycogen level ( J:300001 )

• levels of glycogen are significantly decreased in lungs from early pseudoglandular stage onwards (E14.5) and are 60% lower than controls at E18.5

• lungs of surviving pups show a 20% reduction in glycogen content

• lungs of dead pups contain about 50% of glycogen of wild-type pups

• however, glycogen content is normal is surviving adults

increased skeletal muscle glycogen level ( J:244440 )

• at 15-20 weeks of age, male mice show a 4-fold increase of glycogen levels in skeletal muscle relative to wild-type controls

• glycogen granules isolated from skeletal muscle are larger and extend over a wide range of sizes, with up to a 4-fold greater radius than that in wild-type controls

• EM revealed accumulation of large glycogen particles in the intermyofibrillar space of skeletal (quadriceps) muscle

• both soleus and EDL muscles show increased glycogen levels relative to wild-type muscles, with no significant difference in muscle weights

• however, no changes in the proportion of fiber types are observed in soleus and EDL muscles

abnormal response to exercise ( J:244440 )

• at the point of exhaustion following treadmill exercise, mice show a greater (~2-fold) reduction of glycogen content in skeletal muscle than wild-type controls, suggesting an overall glycolytic shift in muscle metabolism

behavior/neurological

impaired exercise endurance ( J:244440 )

• in spite of increased skeletal muscle glycogen level, mice reach exhaustion earlier than wild-type controls in a treadmill endurance test

decreased aerobic running capacity ( J:244440 )

• mice cover a shorter distance than wild-type controls in a treadmill endurance test

cellular

abnormal cellular respiration ( J:244440 )

• adult soleus muscle exhibits lower oxygen consumption affecting all mitochondrial states; these lower levels are comparable to those in wild-type fast-twitch EDL muscle

• AMP/ATP and ADP/ATP ratios are decreased in soleus muscle, approaching those found in wild-type EDL muscle

• soleus muscle shows no reduction in mitochondrial number or OXPHOS proteins

• EDL muscle shows normal oxygen consumption values with no change in AMP/ATP and ADP/ATP ratios

abnormal lipid oxidation ( J:244440 )

• adult mice show decreased lipid oxidation esp. during the light phase

cardiovascular system

increased cardiac muscle glycogen level ( J:244440 )

• at 15-20 weeks of age, male mice show a 7-fold increase of glycogen levels in cardiac muscle relative to wild-type controls

congestive heart failure ( J:244440 )

• most homozygotes die shortly after birth due to cardiorespiratory failure

respiratory system

abnormal lung morphology ( J:300001 )

• lungs show reduced presence of SP-B and SP-C surfactant proteins

• non-surviving pups show altered surfactant proteins SP-B and SP-C distribution

• however, lung morphology is preserved at E14.5 and at the saccular stage (E18.5), and no differences in cell morphology or apoptosis are seen in lungs at E18.5 and lung morphology and SP-B and SP-C levels are normal is surviving adults

decreased lung glycogen level ( J:300001 )

• levels of glycogen are significantly decreased in lungs from early pseudoglandular stage onwards (E14.5) and are 60% lower than controls at E18.5

• lungs of surviving pups show a 20% reduction in glycogen content

• lungs of dead pups contain about 50% of glycogen of wild-type pups

• however, glycogen content is normal is surviving adults

abnormal type II pneumocyte morphology ( J:300001 )

• accumulation of multivascular bodies (pre-lamellar body organelles), composite bodies (an intermediate organelle containing both vesicles and lamellae) and mitochondria in the cytoplasm of type II pneumocytes

• however, type II pneumocytes of the lungs contain lamellar bodies with similar structure to those in controls

small alveolar lamellar bodies ( J:300001 )

• lamellar bodies in type II pneumocytes are smaller

atelectasis ( J:300001 )

• sacculi of dead pups are collapsed

thick pulmonary interalveolar septum ( J:300001 )

• surviving pups exhibit open sacculi but have thicker septa and lungs are not expanded to the same extent as in wild-type mice

respiratory distress ( J:300001 )

• most pups show difficulty in breathing upon birth, characterized by rapid and shallow breaths

• most lungs from pups that die sink in water indicating no air-inflation

respiratory failure ( J:244440 , J:300001 )

• most homozygotes die shortly after birth due to cardiorespiratory failure (J:244440)

• pups die due to respiratory failure (J:300001)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
glycogen storage disease XV		DOID:0050579	OMIM:613507	J:300001