Phenotypes associated with this allele

• Allele Symbol: Gja5^tm1Paul
• Allele Name: targeted mutation 1, David L Paul
• Allele ID: MGI:2445466
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Gja5^tm1Paul/Gja5^tm1Paul	either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)	MGI:3621213
hm2	Gja5^tm1Paul/Gja5^tm1Paul	involves: 129S4/SvJae	MGI:4818414
hm3	Gja5^tm1Paul/Gja5^tm1Paul	involves: 129S4/SvJae * C57BL/6	MGI:3664790
ht4	Gja5^tm1Paul/Gja5^+	involves: 129S4/SvJae * C57BL/6	MGI:3664791
cx5	Gja4^tm1Paul/Gja4^tm1Paul Gja5^tm1Paul/Gja5^tm1Paul	involves: 129S4/SvJae * C57BL/6	MGI:3629933

Genotype
MGI:3621213

hm1

• Allelic Composition: Gja5^tm1Paul/Gja5^tm1Paul
• Genetic Background: either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)

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

cardiovascular system

abnormal impulse conducting system conduction ( J:46430 )

• homozygotes exhibit significantly delayed atrioventricular and intraventricular conduction as well as uncoordinated ventricular excitation despite normal heart rates and normal sinus rhythms

• no histological evidence of ventricular hypertrophy or dilation, and no signs of abnormal cardiac orientation are observed

prolonged PR interval ( J:46430 )

• three-lead ECGs indicate that mutant PR intervals are at least 21% longer than wild-type PR intervals, indicating delayed atrioventricular conduction

• prolonged PR intervals associated with a normal sinus rhythm indicate presence of a first-degree atrioventricular block

abnormal frontal plane axis ( J:46430 )

• homozygotes exhibit spatially altered propagation of electrical activity in the ventricles i.e. a significantly wider distribution of frontal plane axes relative to wild-type mice (-130 to + 180 vs -80 to +90), as measured by vectorially summing the QRS amplitudes in limb leads

prolonged P wave ( J:46430 )

• ECGs indicate that mutant P waves are, on average, ~9% longer than wild-type P waves

abnormal QRS complex ( J:46430 )

fragmented QRS complex ( J:46430 )

• mutant ECGs show split QRS complexes in lead II, rSR' morphology in lead III and wide S waves in lead I, indicating uncoordinated ventricular activation

• 90% of homozygotes show either a split QRS complex in lead II or rSR' morphology in lead III compared with 13% of wild-type and 20% of heterozygous mutant mice

prolonged QT interval ( J:46430 )

• mutant ECGs indicate prolonged QT intervals compared with wild-type ECGs

bundle branch block ( J:46430 )

• presence of broad, split or notched QRS complexes associated with frontal plane axis deviation indicate a bundle branch block

prolonged QRS complex duration ( J:46430 )

• mutant three-lead ECGs that mutant QRS complexes are on average 34% longer than wild-type QRS complexes, indicating delayed intraventricular conduction

Genotype
MGI:4818414

hm2

• Allelic Composition: Gja5^tm1Paul/Gja5^tm1Paul
• Genetic Background: involves: 129S4/SvJae

homeostasis/metabolism

increased susceptibility to injury ( J:161949 )

• mice subjected to femoral artery occlusion exhibit reduced hindlimb perfusion, arterial collateral diameters, and fewer growing collaterals compared with similarly treated wild-type mice

• mice subjected to femoral artery occlusion exhibit reduced flow-driven outward remodeling response compared with similarly treated wild-type mice

• mice subjected to chronic blood flow increase in mesenteric resistance arteries exhibit smaller increased in arterial diameters compared with similarly treated wild-type mice

Genotype
MGI:3664790

hm3

• Allelic Composition: Gja5^tm1Paul/Gja5^tm1Paul
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

neonatal lethality, incomplete penetrance ( J:109301 )

• homozygotes born of heterozygous crosses survive the neonatal period; in contrast, 3 of 50 homozygotes obtained from homozygous crosses die shortly after birth with severe cardiac malformations (double-outlet right ventricle, dilated and hypertrophic cardiomyopathy)

cardiovascular system

pulmonary artery hypoplasia ( J:109301 )

• 1 of the 3 neonatal lethal homozygotes obtained from homozygous crosses exhibited tetralogy of Fallot with pulmonary atresia (severe hypoplasia of the main pulmonary artery with atresia of its origins from the right ventricle)

abnormal heart morphology ( J:109301 )

• 33% of homozygotes born of heterozygous crosses displayed cardiac malformations, none of which were observed in wild-type mice

• notably, homozygotes born of homozygous crosses exhibited a higher frequency of cardiac malformations (44%)

abnormal atrioventricular cushion morphology ( J:109301 )

• 2 of 12 homozygotes born of heterozygous crosses exhibited an unbalanced, partial endocardial cushion defect (ECD), in the absence of a significant ventricular septal defect

• 3 of 39 homozygotes born of homozygous crosses had ECDs, and in one case, DORV plus a mitral valve cleft

double outlet right ventricle ( J:109301 )

• 2 of 12 homozygotes born of heterozygous crosses exhibited variants of double outlet right ventricle (DORV), not observed in wild-type or heterozygous mutant mice

• strikingly, 14 of 39 homozygotes born of homozygous crosses exhibited DORV or tetralogy of Fallot, while 1 of 39 displayed DORV plus ECD

mitral valve stenosis ( J:109301 )

• homozygotes (born of heterozygous crosses) with partial ECDs exhibited severe mitral stenosis

common atrioventricular valve ( J:109301 )

• homozygotes (born of heterozygous crosses) with partial ECDs showed a common atrioventricular valve with papillary muscle attachments within both ventricles

ostium primum atrial septal defect ( J:109301 )

• homozygotes (born of heterozygous crosses) with partial ECDs had a very large ostium primum atrial septal defect

dilated cardiomyopathy ( J:109301 )

• 1 of 39 homozygotes born of homozygous crosses showed dilated cardiomyopathy plus hypertrophy

muscle

dilated cardiomyopathy ( J:109301 )

• 1 of 39 homozygotes born of homozygous crosses showed dilated cardiomyopathy plus hypertrophy

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
tetralogy of Fallot		DOID:6419	OMIM:187500	J:109301

Genotype
MGI:3664791

ht4

• Allelic Composition: Gja5^tm1Paul/Gja5⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6

cardiovascular system

abnormal aortic arch and aortic arch branch attachment ( J:109301 )

• 1 of 33 heterozygous newborns displayed an aortic arch branch vessel abnormality, whereby the take-off of two branch vessels from the aorta was more proximal than normal and the left vessel coursed leftward and laterally

abnormal heart morphology ( J:109301 )

• 6 of 33 (18%) heterozygous fetuses or neonates displayed cardiac malformations, none of which were observed in wild-type mice

bifid atrial appendage ( J:109301 )

• at E18.5, 3 of 33 heterozygotes exhibited a bifid atrial appendage (one in the right atrium, two in the left atrium), not observed in any wild-type or homozygous mutant mice

• notably, one heterozygous heart presented both bifid atrial appendage and tetralogy of Fallot

ventricular septal defect ( J:109301 )

• 2 of 33 heterozygotes displayed isolated ventricular septal defects

• 1 of 33 heterozygotes exhibited both bifid atrial appendage and tetralogy of Fallot

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
tetralogy of Fallot		DOID:6419	OMIM:187500	J:109301

Genotype
MGI:3629933

cx5

• Allelic Composition: Gja4^tm1Paul/Gja4^tm1Paul; Gja5^tm1Paul/Gja5^tm1Paul
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

lethality throughout fetal growth and development, incomplete penetrance ( J:80178 )

• incomplete penetrance; reduced embryonic viability at E14.5

neonatal lethality, incomplete penetrance ( J:80178 )

• animals died within 2 days after birth

postnatal lethality, complete penetrance ( J:80178 )

• animals died within 2 days after birth

reproductive system

abnormal testis morphology ( J:80178 )

♂ • extensive blood filled region of testes; congested, thin walled vascular channels in between testicular cord tissue

abnormal spermatogenesis ( J:80178 )

♂ • mild to severe sperm vacuolar degeneration and necrosis

cardiovascular system

blood vessel congestion ( J:80178 )

lung hemorrhage ( J:80178 )

• 45% of animals displayed blood-filled lungs

gastrointestinal hemorrhage ( J:80178 )

• enlarged blood vessels in intestinal or gastric wall

increased vasodilation ( J:80178 )

• dilated blood vessels observed in skin near hematomas; subcutaneous hematomas observed on dorsal surface of the animal, especially on the head and also on the neck, shoulders, and posterior regions

digestive/alimentary system

gastrointestinal hemorrhage ( J:80178 )

• enlarged blood vessels in intestinal or gastric wall

respiratory system

lung hemorrhage ( J:80178 )

• 45% of animals displayed blood-filled lungs

endocrine/exocrine glands

abnormal testis morphology ( J:80178 )

♂ • extensive blood filled region of testes; congested, thin walled vascular channels in between testicular cord tissue

muscle

increased vasodilation ( J:80178 )

• dilated blood vessels observed in skin near hematomas; subcutaneous hematomas observed on dorsal surface of the animal, especially on the head and also on the neck, shoulders, and posterior regions