cardiovascular system phenotype

• abnormal tricuspid valve morphology
  • 17% show cleft tricuspid valve
  (MGI Ref ID J:35363)

• failure of atrioventricular cushion closure
  • complete lack of fusion of the superior and inferior atroioventricular cushions
  (MGI Ref ID J:35363)

• muscular ventricular septal defect
  • 94% exhibit a ventricular septal defect, with all defects being muscular
  (MGI Ref ID J:35363)
  • by E14.5, 9 of 10 homozygotes display obvious ventricular septal defects at the septal-cushion fusion
  (MGI Ref ID J:18047)
  • at E14.5, homozygotes display a poorly developed ventricular septum
  (MGI Ref ID J:18047)(MGI Ref ID J:65904)

• thin ventricular wall
  (MGI Ref ID J:35363)
  • at E13.5, the relatively thin-walled "atrial-like" phenotype of mutant ventricular muscle cells is shown to correlate with the aberrant, persistent expression of an atrial marker
  (MGI Ref ID J:18047)
  • at E14.5, all (10 of 10) homozygotes exhibit a thinned ventricular wall
  (MGI Ref ID J:18047)

• abnormal heart left atrium morphology
  • at E14.5, homozygotes exhibit normal atrial structure and function with no differences in overall position of heart and major vessels; however, the left atrium appears small
  (MGI Ref ID J:65904)

• abnormal myocardium layer morphology
  • spongy layer of the myocardium is generally thicker
  (MGI Ref ID J:35363)
  • all homozygotes display impaired differentiation or maturation of the ventricular cardiac myocytes
  (MGI Ref ID J:18047)

• aortopulmonary window
  • 28% show incomplete aorticopulmonary septum/aorticopulmonary window
  (MGI Ref ID J:35363)

• decreased heart rate
  • at E13.5, homozygotes show normal AV synchrony and display heart rates comparable to those of wild-type mice; however, mutant heart rates are slightly decreased at E14.5
  (MGI Ref ID J:65904)

• dilated heart atrium
  • at E14.5, 5 of 10 homozygotes display dilation of the right atrial chambers
  (MGI Ref ID J:18047)

• heart block
  • at E14.5, 2 of 10 homozygotes display a complete heart block
  (MGI Ref ID J:65904)

• persistent truncus arteriosis
  • seen in 11% of homozygotes
  (MGI Ref ID J:35363)

• trabecula carnea hypoplasia
  • by E14.5, ventricular trabeculation is present but reduced and appears disorganized at the muscular septum
  (MGI Ref ID J:18047)

• abnormal pericardium morphology
  • at E11.5 and E12.5, homozygotes exhibit a loosely apposed pericardium; however, the pericardium appears relatively normal at E14.5
  (MGI Ref ID J:18047)

• abnormal truncus arteriosus septation
  • at E14.5, only 1 of 10 homozygotes displays an abnormal aortic pulmonary septum; both aortic and pulmonary valves appear unaffected
  (MGI Ref ID J:18047)

• abnormal heart morphology
  • at E13.5, upon color fluorescent imaging, the mutant heart appears much more translucent than the wild-type heart
  (MGI Ref ID J:65904)

• abnormal myocardium compact layer morphology
  • by E14.5, homozygotes show absence of myocyte proliferation at the ventricular epicardial surface ("compact layer")
  (MGI Ref ID J:18047)

• congestive heart failure
  (MGI Ref ID J:65904)
  • homozygotes appear to die in utero as a result of congestive heart failure
  (MGI Ref ID J:18047)

• dilated heart right ventricle
  • at E14.5, some homozygotes display dilated right ventricles
  (MGI Ref ID J:18047)

• abnormal ventricle papillary muscle morphology
  • 56% exhibit dysmorphic papillary muscles
  (MGI Ref ID J:35363)

• complete atrioventricular septal defect
  • 39% show a common atrioventricular canal
  (MGI Ref ID J:35363)

• ventricular myocardium compact layer hypoplasia
  • 94% exhibit a hypoplastic compact zone of the ventricular myocardium
  (MGI Ref ID J:35363)

• decreased cardiac output
  (MGI Ref ID J:65904)

• double outlet right ventricle
  • portion of embryos with shortened conotruncal ridges exhibit double outlet right ventricle (17%)
  (MGI Ref ID J:35363)

• ventricular hypoplasia
  • by E14.5, all (10 of 10) homozygotes show ventricular chamber hypoplasia
  (MGI Ref ID J:18047)

• abnormal atrioventricular cushion morphology
  • 67% show partial fusion of the atrioventricular cushions
  (MGI Ref ID J:35363)
  • exhibit a wide spectrum of atrioventricular cushion defects
  (MGI Ref ID J:35363)

• abnormal conotruncal ridge morphology
  • 100% have abnormalities of conotruncal ridges ranging from mild deficiency of conotruncal tissue (6%) to complete absence of cushion tissue (66%)
  (MGI Ref ID J:35363)

• abnormal heart ventricle morphology
  • at E11.5 or later, homozygotes exhibit an uneven ventricular contour
  (MGI Ref ID J:18047)
  • at E14.5, both ventricles exhibit a globular rather than elliptical shape, suggesting a dilated form of congestive heart failure
  (MGI Ref ID J:65904)

• decreased ventricle muscle contractility
  • at E13.5 and E14.5, left ventricular area ejection fractions of mutant hearts average 14% vs 50% in wild-type hearts, indicating ventricular dysfunction
  (MGI Ref ID J:65904)
  • at E14.5, depressed ejection fraction is related to thinned left ventricular wall and impaired shortening of the mutant myocardium
  (MGI Ref ID J:65904)

• abnormal mitral valve morphology
  • 17% show cleft mitral valve
  (MGI Ref ID J:35363)

• abnormal myocardial trabeculae morphology
  • 67% show attenuated trabeculae and contain an unusual, random branching pattern
  (MGI Ref ID J:35363)

• abnormal pericardial cavity morphology
  • by E14.5, most homozygotes show a prominent pericardial space
  (MGI Ref ID J:18047)

• atrioventricular block
  • by E14.5, homozygotes with slightly reduced heart rates exhibit an intermittent partial AV block (not quantified)
  (MGI Ref ID J:65904)

• mitral valve atresia
  • by E14.4, 1 of 10 homozygotes displays mitral atresia; no tricuspid atresia is observed
  (MGI Ref ID J:18047)

cellular phenotype

• decreased hepatocyte proliferation
  • at E12.5, homozygotes exhibit a marked reduction in hepatocyte proliferation with substantial recovery to ~60% of wild-type values noted at E14.5
  (MGI Ref ID J:18047)

homeostasis/metabolism phenotype

• skin edema
  • at E14.5, homozygotes display a dramatic subdermal edema, that is most prominent along the back and in the folds of skin around the eye
  (MGI Ref ID J:18047)
  • however, most major organ systems, including the intestine, skin, kidney and eye, appear normal
  (MGI Ref ID J:18047)

integument phenotype

• translucent skin
  (MGI Ref ID J:18047)

• skin edema
  • however, most major organ systems, including the intestine, skin, kidney and eye, appear normal
  (MGI Ref ID J:18047)
  • at E14.5, homozygotes display a dramatic subdermal edema, that is most prominent along the back and in the folds of skin around the eye
  (MGI Ref ID J:18047)

liver/biliary system phenotype

• small liver
  • at E12.5, homozygotes display a liver mass that is ~30% of wild-type mice in the absence of morphological defects
  (MGI Ref ID J:18047)

• delayed hepatic development
  (MGI Ref ID J:18047)

• decreased hepatocyte proliferation
  • at E12.5, homozygotes exhibit a marked reduction in hepatocyte proliferation with substantial recovery to ~60% of wild-type values noted at E14.5
  (MGI Ref ID J:18047)

mortality/aging

• lethality throughout fetal growth and development, complete penetrance
  • homozygotes die between E13.5 and E16.5, with most embryos still viable at E14.5 but dead by E15.5
  (MGI Ref ID J:18047)

muscle phenotype

• abnormal myocardium layer morphology
  • spongy layer of the myocardium is generally thicker
  (MGI Ref ID J:35363)
  • all homozygotes display impaired differentiation or maturation of the ventricular cardiac myocytes
  (MGI Ref ID J:18047)

• abnormal ventricle papillary muscle morphology
  • 56% exhibit dysmorphic papillary muscles
  (MGI Ref ID J:35363)

• decreased ventricle muscle contractility
  • at E14.5, depressed ejection fraction is related to thinned left ventricular wall and impaired shortening of the mutant myocardium
  (MGI Ref ID J:65904)
  • at E13.5 and E14.5, left ventricular area ejection fractions of mutant hearts average 14% vs 50% in wild-type hearts, indicating ventricular dysfunction
  (MGI Ref ID J:65904)

• trabecula carnea hypoplasia
  • by E14.5, ventricular trabeculation is present but reduced and appears disorganized at the muscular septum
  (MGI Ref ID J:18047)

• ventricular myocardium compact layer hypoplasia
  • 94% exhibit a hypoplastic compact zone of the ventricular myocardium
  (MGI Ref ID J:35363)

• abnormal myocardium compact layer morphology
  • by E14.5, homozygotes show absence of myocyte proliferation at the ventricular epicardial surface ("compact layer")
  (MGI Ref ID J:18047)

• abnormal myocardial trabeculae morphology
  • 67% show attenuated trabeculae and contain an unusual, random branching pattern
  (MGI Ref ID J:35363)

cardiovascular system phenotype

• abnormal atrioventricular valve morphology
  • atrioventricular cushion defects range from absent fusion (3%) and hypoplasia (8%) to abnormalities of mature valvular structures
  (MGI Ref ID J:35363)

• double outlet right ventricle
  • seen in 5% of heterozygotes
  (MGI Ref ID J:35363)

• abnormal heart ventricle morphology
  (MGI Ref ID J:35363)

• abnormal myocardial trabeculae morphology
  • 49% show trabecular defects with less organized trabecular arrangement
  (MGI Ref ID J:35363)

• abnormal tricuspid valve morphology
  • 8% show tricuspid valve abnormalities
  (MGI Ref ID J:35363)

• abnormal ventricle papillary muscle morphology
  • 86% show papillary muscle defects
  (MGI Ref ID J:35363)

• thin ventricular wall
  • thin left ventricle wall is associated with mitral valve stenosis yet a normal right ventricle and semilunar valves
  (MGI Ref ID J:35363)
  • severe thinning of the ventricular wall is seen in both the left (2%) and right (2%) ventricles, but never simultaneously
  (MGI Ref ID J:35363)
  • thin right ventricle is associated with dysmorphic tricuspid valve yet normal left-sided and semilunar structures
  (MGI Ref ID J:35363)

• abnormal heart development
  • 15% exhibit conotruncal defects, with severity ranging from absent conotruncal ridges (3%) to a shortened conotruncal septum (7%)
  (MGI Ref ID J:35363)

• abnormal mitral valve morphology
  • 17% show cleft mitral valve
  (MGI Ref ID J:35363)

• mitral valve stenosis
  • 2% show mitral valve stenosis
  (MGI Ref ID J:35363)

• abnormal myocardium layer morphology
  (MGI Ref ID J:35363)

• abnormal interventricular septum morphology
  (MGI Ref ID J:35363)

• abnormal myocardium compact layer morphology
  • intermediate thickness of compact layer compared to homozygotes and wild-type, especially prominent at E13.5 and 14.5
  (MGI Ref ID J:35363)

• pulmonary artery stenosis
  • one heterozygote shows pulmonary artery stenosis
  (MGI Ref ID J:35363)

muscle phenotype

• abnormal ventricle papillary muscle morphology
  • 86% show papillary muscle defects
  (MGI Ref ID J:35363)

• abnormal myocardial trabeculae morphology
  • 49% show trabecular defects with less organized trabecular arrangement
  (MGI Ref ID J:35363)

• abnormal myocardium compact layer morphology
  • intermediate thickness of compact layer compared to homozygotes and wild-type, especially prominent at E13.5 and 14.5
  (MGI Ref ID J:35363)

• abnormal myocardium layer morphology
  (MGI Ref ID J:35363)