Phenotypes associated with this allele

• Allele Symbol: Ada^tm1Mw
• Allele Name: targeted mutation 1, Maki Wakamiya
• Allele ID: MGI:1857117
• Summary: 7 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Ada^tm1Mw/Ada^tm1Mw	involves: 129S7/SvEvBrd	MGI:3812473
hm2	Ada^tm1Mw/Ada^tm1Mw	involves: 129S7/SvEvBrd * C57BL/6	MGI:2183043
hm3	Ada^tm1Mw/Ada^tm1Mw	involves: 129S7/SvEvBrd * C57BL/6 * FVB/N	MGI:2168183
cx4	Ada^tm1Mw/Ada^tm1Mw Adora2b^tm1Dgen/Adora2b^tm1Dgen Tg(Afp-ADA)#Xiay/0	involves: 129P2/OlaHsd * 129S7/SvEvBrd * C3H/HeJ * C57BL/6J	MGI:5897419
cx5	Ada^tm1Mw/Ada^tm1Mw Tg(Afp-ADA)#Xiay/0	involves: 129S7/SvEvBrd * C3H/HeJ * C57BL/6J	MGI:5897391
cx6	Ada^tm1Mw/Ada^tm1Mw Tg(PLADA)4118Rkmb/0	involves: 129S7/SvEvBrd * C57BL/6	MGI:2683994
cx7	Ada^tm1Mw/Ada^tm1Mw Tg(PLFSADA)2465Rkmb/0	involves: 129S7/SvEvBrd * C57BL/6 * FVB/N	MGI:2682599

Genotype
MGI:3812473

hm1

• Allelic Composition: Ada^tm1Mw/Ada^tm1Mw
• Genetic Background: involves: 129S7/SvEvBrd

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

growth/size/body

heart right ventricle hypertrophy ( J:231559 )

• mice develop right ventricle hypertrophy

• treatment with GS-6201 reduces right ventricle hypertrophy

cellular

increased vascular smooth muscle cell proliferation ( J:231559 )

• increase in proliferation of cells within the vascular wall of the lungs

maternal effect ( J:234143 )

• fetuses from pregnant mutant females are smaller and weigh less

cardiovascular system

abnormal lung vasculature morphology ( J:231559 )

• mice exhibit vascular remodeling in the lung

• increase in muscularization of vessels and a greater number of muscularized vessels are seen in the lung parenchyma

• treatment with GS-6201 inhibits the extent of muscularization but not the number of muscularized vessels

abnormal placenta vasculature ( J:234143 )

♀ • placentas show disorganized and impaired vasculature in the labyrinthine zone

♀ • treatment with adenosine deaminase enzyme therapy ameliorates placental defects

vascular smooth muscle hypertrophy ( J:231559 )

• thickening of the vascular smooth muscle wall in the lungs

• treatment with the ADORA2B antagonist GS-6201 reduces the thickening of the vascular smooth muscle wall

heart right ventricle hypertrophy ( J:231559 )

• mice develop right ventricle hypertrophy

• treatment with GS-6201 reduces right ventricle hypertrophy

increased right ventricle systolic pressure ( J:231559 )

• mice develop increased right ventricle systolic pressure

• treatment with GS-6201 reduces right ventricle systolic pressure

pulmonary hypertension ( J:231559 )

• mice exhibit hallmarks of pulmonary hypertension

• treatment with GS-6201 reduces the hallmarks of pulmonary hypertension

increased vascular smooth muscle cell proliferation ( J:231559 )

• increase in proliferation of cells within the vascular wall of the lungs

immune system

increased dendritic cell number ( J:138722 )

• the number of proangiogenic CD11b^lowCD11c+ dendritic cells in the lungs is increased by 3-fold and they exhibit increased size compared to in wild-type mice

abnormal dendritic cell physiology ( J:138722 )

• lung dendritic cells exhibit increased basal secretion levels of VEGF and CXCL1 and elevated VEGF production in response to NECA compared to in wild-type mice

embryo

abnormal placenta morphology ( J:234143 )

♀ • increase in placental adenosine levels

♀ • treatment with adenosine deaminase enzyme therapy reduces placental adenosine levels and ameliorates placental defects

abnormal placenta vasculature ( J:234143 )

♀ • placentas show disorganized and impaired vasculature in the labyrinthine zone

♀ • treatment with adenosine deaminase enzyme therapy ameliorates placental defects

small placenta ( J:234143 )

♀

decreased placenta weight ( J:234143 )

♀

hematopoietic system

increased dendritic cell number ( J:138722 )

• the number of proangiogenic CD11b^lowCD11c+ dendritic cells in the lungs is increased by 3-fold and they exhibit increased size compared to in wild-type mice

muscle

vascular smooth muscle hypertrophy ( J:231559 )

• thickening of the vascular smooth muscle wall in the lungs

• treatment with the ADORA2B antagonist GS-6201 reduces the thickening of the vascular smooth muscle wall

heart right ventricle hypertrophy ( J:231559 )

• mice develop right ventricle hypertrophy

• treatment with GS-6201 reduces right ventricle hypertrophy

increased vascular smooth muscle cell proliferation ( J:231559 )

• increase in proliferation of cells within the vascular wall of the lungs

respiratory system

abnormal lung vasculature morphology ( J:231559 )

• mice exhibit vascular remodeling in the lung

• increase in muscularization of vessels and a greater number of muscularized vessels are seen in the lung parenchyma

• treatment with GS-6201 inhibits the extent of muscularization but not the number of muscularized vessels

abnormal pulmonary alveolar system morphology ( J:231559 )

• mice show airspace enlargement

• treatment with the ADORA2B antagonist GS-6201reduces airspace enlargement

increased lung elastance ( J:231559 )

• lung elastance is increased

• treatment with GS-6201 inhibits the changes in lung function

increased airway resistance ( J:231559 )

• lung resistance is increased

• treatment with GS-6201 inhibits the changes in lung function

decreased lung compliance ( J:231559 )

• lung compliance is reduced

• treatment with GS-6201inhibits the changes in lung function

abnormal pulmonary gas exchange ( J:231559 )

• mice show decreased levels of arterial oxygen saturation compared with controls

• treatment with GS-6201 inhibits the decreased levels of arterial oxygenation; improves gas exchange in the lung

Genotype
MGI:2183043

hm2

• Allelic Composition: Ada^tm1Mw/Ada^tm1Mw
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

Hepatocyte abnormalities in Ada^tm1Mw/Ada^tm1Mw mice

cellular

increased hepatocyte karyomegaly ( J:25085 )

• enlarged hepatocytes with karyomegaly as early as E16.5

mortality/aging

neonatal lethality, complete penetrance ( J:25085 )

• animals die at birth or shortly thereafter

• only 10% born with beating hearts, but these animals did not move

growth/size/body

decreased body weight ( J:25085 )

• 15% smaller than littermates

homeostasis/metabolism

decreased circulating serum albumin level ( J:25085 )

• 57% reduction

decreased circulating total protein level ( J:25085 )

• 59% reduction

cyanosis ( J:25085 )

• pups born with beating hearts remained cyanotic until death a few hours later

abnormal enzyme/coenzyme level ( J:25085 )

• elevated levels of hepatocellular enzymes, aspartate aminotransferase (66%) and alanine aminotransferase (56%)

abnormal nucleotide metabolism ( J:25085 )

• dATP levels in fetal blood are elevated 2000-fold while ATP levels are decreased slightly

immune system

decreased T cell number ( J:25085 )

• decreased numbers of mature T lymphocytes

liver/biliary system

abnormal liver morphology ( J:25085 )

• livers have disorganized hepatic plates, resulting in isolated packets of cells

abnormal hepatocyte morphology ( J:25085 )

• morphological changes in hepatocytes are seen as early as E16.5, including enlarged hepatocytes with karyomegaly, irregularly shaped nuclear envelopes, and a decrease in heterochromatin

• cytoplasm of hepatocytes has decreased amounts of glycogen and increased volume of rough ER

• hepatocytes lose their normal polyhedral shape and become round

increased hepatocyte karyomegaly ( J:25085 )

• enlarged hepatocytes with karyomegaly as early as E16.5

decreased hepatocyte number ( J:25085 )

• decrease in numbers of hepatocytes per lobule

small liver ( J:25085 )

• 29% smaller than littermates

hepatic necrosis ( J:25085 )

• evident at E17.5

hematopoietic system

decreased T cell number ( J:25085 )

• decreased numbers of mature T lymphocytes

Genotype
MGI:2168183

hm3

• Allelic Composition: Ada^tm1Mw/Ada^tm1Mw
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6 * FVB/N

reproductive system

abnormal penile erection ( J:135978 )

♂ • mice exhibit increased corpus cavernosal smooth muscle relaxation in response to nerve stimulation

priapism ( J:135978 )

♂ • mice exhibit erections lasting up to 72 hours that is associated with increased camp and cGMP production

♂ • however, treatment with PEG-ADA corrects the observed priapism

♂ • mice exhibit penile vascular damage, including marked intimal thickening with smooth muscle hypertrophy and endothelial swelling, and fibrosis subsequent to priapism

Genotype
MGI:5897419

cx4

• Allelic Composition: Ada^tm1Mw/Ada^tm1Mw; Adora2b^tm1Dgen/Adora2b^tm1Dgen; Tg(Afp-ADA)#Xiay/0
• Genetic Background: involves: 129P2/OlaHsd * 129S7/SvEvBrd * C3H/HeJ * C57BL/6J

cardiovascular system

cardiovascular system phenotype ( J:234143 )

♀N • preeclampsia features seen in Ada^tm1Mw/Ada^tm1Mw Tg(Afp-ADA)#Xiay/0 dams, including hypertension are ameliorated

renal/urinary system

renal/urinary system phenotype ( J:234143 )

♀N • preeclampsia features seen in Ada^tm1Mw/Ada^tm1Mw Tg(Afp-ADA)#Xiay/0 dams dams, including proteinuria and renal changes are ameliorated

embryo

abnormal placenta morphology ( J:234143 )

♀ • mice exhibit an increase in placental adenosine levels

♀ • however, placental weight is increased and placental vasculature is more organized and uniform compared to Ada^tm1Mw/Ada^tm1Mw Tg(Afp-ADA)#Xiay/0 mice

Genotype
MGI:5897391

cx5

• Allelic Composition: Ada^tm1Mw/Ada^tm1Mw; Tg(Afp-ADA)#Xiay/0
• Genetic Background: involves: 129S7/SvEvBrd * C3H/HeJ * C57BL/6J

mortality/aging

postnatal lethality, complete penetrance ( J:234143 )

• mice die by 3 weeks of age because hepatic production of ADA subsides during the first week following birth

• however, treatment with adenosine deaminase enzyme replacement therapy prevents this lethality and the phenotypes described are with mice that have been treated with the replacement therapy from birth

cellular

maternal effect ( J:234143 )

• fetuses from mutant pregnant females are smaller and weigh less

cardiovascular system

abnormal placenta vasculature ( J:234143 )

♀ • pregnant mice show impaired placental vasculature and reduced CD31+ vessels in the placenta

hypertension ( J:234143 )

♀ • dams develop preeclampsia

increased systemic arterial systolic blood pressure ( J:234143 )

♀ • dams show an increase in mean systolic blood pressure late in pregnancy beginning on E15.5, which remains elevated through E17.5 and returns to normal by day 5 postpartum

♀ • mean arterial pressure is elevated on E18.5 in dams

embryo

abnormal placenta morphology ( J:234143 )

♀ • pregnant mice exhibit elevated placental adenosine levels at E12.5 that remain elevated through E18.5

abnormal placenta vasculature ( J:234143 )

♀ • pregnant mice show impaired placental vasculature and reduced CD31+ vessels in the placenta

small placenta ( J:234143 )

♀

decreased placenta weight ( J:234143 )

♀

homeostasis/metabolism

increased urine protein level ( J:234143 )

♀ • urinary protein (ratio of albumin/creatinine) is elevated on E18.5 but not on E12.5, and this proteinuria is reduced to normal levels by postpartum day 7

renal/urinary system

increased urine protein level ( J:234143 )

♀ • urinary protein (ratio of albumin/creatinine) is elevated on E18.5 but not on E12.5, and this proteinuria is reduced to normal levels by postpartum day 7

abnormal renal glomerulus morphology ( J:234143 )

♀ • swollen glomeruli with narrowed capillary and Bowmans spaces in pregnant mice

♀ • pregnant mice show glomerular endotheliosis

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
pre-eclampsia		DOID:10591	OMIM:189800 OMIM:609402 OMIM:609403 OMIM:609404 OMIM:614592	J:234143

Genotype
MGI:2683994

cx6

• Allelic Composition: Ada^tm1Mw/Ada^tm1Mw; Tg(PLADA)4118Rkmb/0
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

Structural alterations in the thymus and spleen of Ada^tm1Mw/Ada^tm1Mw Tg(PLADA)4118Rkmb/0 mice

mortality/aging

postnatal lethality, complete penetrance ( J:73418 , J:234143 )

• death by 3 weeks of age (J:73418)

• following birth and removal of the placenta, mice die within 3 weeks from severe pulmonary impairment due to excessive accumulation of adenosine (J:234143)

• however, treatment with adenosine deaminase enzyme replacement therapy prevents this lethality and the phenotypes described are with mice that have been treated with the replacement therapy from birth (J:234143)

hematopoietic system

abnormal thymus corticomedullary boundary morphology ( J:73418 )

• with decreased cortical-medullary demarcation

small thymus ( J:73418 )

increased double-negative T cell number ( J:73418 )

• in thymus

anemia ( J:73418 )

increased granulocyte number ( J:73418 )

increased eosinophil cell number ( J:73418 )

increased macrophage cell number ( J:73418 )

decreased leukocyte cell number ( J:73418 )

decreased double-positive T cell number ( J:73418 )

• in both thymus and spleen

abnormal spleen red pulp morphology ( J:73418 )

• with decreased numbers of red blood cells and few megakaryocytes observed

small spleen ( J:73418 )

spleen hypoplasia ( J:73418 )

• lymphoid counts substantially reduced

decreased immunoglobulin level ( J:73418 )

immune system

abnormal thymus corticomedullary boundary morphology ( J:73418 )

• with decreased cortical-medullary demarcation

small thymus ( J:73418 )

increased double-negative T cell number ( J:73418 )

• in thymus

increased granulocyte number ( J:73418 )

increased eosinophil cell number ( J:73418 )

increased macrophage cell number ( J:73418 )

decreased leukocyte cell number ( J:73418 )

decreased double-positive T cell number ( J:73418 )

• in both thymus and spleen

abnormal spleen red pulp morphology ( J:73418 )

• with decreased numbers of red blood cells and few megakaryocytes observed

small spleen ( J:73418 )

spleen hypoplasia ( J:73418 )

• lymphoid counts substantially reduced

decreased immunoglobulin level ( J:73418 )

lung inflammation ( J:73418 )

• evidence of inflammatory cells, thickening and shedding of airway epithelium and occlusion of airways with mucous and cellular debris

renal/urinary system

renal/urinary system phenotype ( J:234143 )

♀N • proteinuria and kidney abnormalities are abolished

abnormal renal glomerulus morphology ( J:73418 )

• increased red blood cells within glomeruli

abnormal renal tubule morphology ( J:73418 )

• increased red blood cells within convoluted tubules

respiratory system

lung inflammation ( J:73418 )

• evidence of inflammatory cells, thickening and shedding of airway epithelium and occlusion of airways with mucous and cellular debris

tachypnea ( J:73418 )

• evident beginning at postnatal day 12 and progressively labored breathing until death

skeleton

abnormal costochondral joint morphology ( J:73418 )

• enlarged costochondral junctions

abnormal rib morphology ( J:73418 )

• severe rib curvature

endocrine/exocrine glands

abnormal thymus corticomedullary boundary morphology ( J:73418 )

• with decreased cortical-medullary demarcation

small thymus ( J:73418 )

cardiovascular system

cardiovascular system phenotype ( J:234143 )

♀N • hypertension is abolished

embryo

embryo phenotype ( J:234143 )

♀N • placental adenosine levels are restored to normal levels, placental weights and vasculature are normal, and fetal weights from mutant dams are normal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
adenosine deaminase deficiency		DOID:5810	OMIM:102700	J:73418

Genotype
MGI:2682599

cx7

• Allelic Composition: Ada^tm1Mw/Ada^tm1Mw; Tg(PLFSADA)2465Rkmb/0
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6 * FVB/N

normal phenotype

no abnormal phenotype detected ( J:29350 )

• no hepatocellular damage; rescued from perinatal lethality seen in homozygous mice

• rescue from severe, perinatally lethal respiratory distress seen in mice homozygous for Ada^tm1Mw