Mouse Genome Informatics
hm1
    Ece1tm1Reh/Ece1tm1Reh
involves: 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• most embryos die prior to E13.5
• Background Sensitivity: 100% embryonic lethal in a pure 129S/SvEv background


Mouse Genome Informatics
hm2
    Ece1tm1Reh/Ece1tm1Reh
involves: 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• those mutants that do survive to term die within 30 minutes of birth
• Background Sensitivity: 75% embryonic lethal in a C57BL/6-129/SvEv hybrid background
• most embryos die before E13.5

pigmentation
• the neural crest derived melanocytes of the choroid and Harderian gland are absent
• there are no detectable melanocytes in the dorsal skin of term mutants

cardiovascular system
• the peripheral vessels are congested and dilated
• interruption of the aortic arch is observed at birth (18 out of 31)
• the right subclavian artery is absent (7 out of 31)
• the endocardial cushions are poorly developed
• the aorta arises from the right ventricle resulting in double outlet right ventricle (3 out of 10)
• the aorta overrides the crest of the ventricular septum in 5 out 10 pups
• ventricular septal defects are found in 100% (10 out of 10) of mutant embryos at birth
• the atria are congested and dilated
• along with dilation of the peripheral vasculature this is consistent with cardiac failure
• peripheral vascular dilation is seen in premorbid embryos

craniofacial
• the alisphenoid cone is hypoplastic and deformed
• the squamosal bone is hypoplastic and deformed
• the styloid process is severely deformed
• at birth the mandible is markedly reduced in size
• the teeth are normal however the lower incisors are embedded in loose mesenchyme rather than the mandible
• the palatine bone is hypoplastic and deformed
• the cartilaginous rudiment of the stapes is absent in 11 out of 14 embryos
• at birth Meckel's cartilage is absent
• at birth most of the tongue is absent
• the external auditory meatus is absent

endocrine/exocrine glands
• at birth many of the submandibular and sublingual ducts are missing
• the parathyroid glands are hypoplastic

hearing/vestibular/ear
• the cartilaginous rudiment of the stapes is absent in 11 out of 14 embryos
• the external auditory meatus is absent
• the tympanic ring is absent

homeostasis/metabolism
• along with dilation of the peripheral vasculature this is consistent with cardiac failure
• generalized edema is seen in premorbid embryos

immune system
• the thymus does not fully descend into the thoracic cavity

muscle
• peripheral vascular dilation is seen in premorbid embryos

skeleton
• the ventral neck is sunken
• at birth fusion of the hyoid bone, thyroid cartilage and the basiphenoid bone, is seen resulting in a narrower airway
• the alisphenoid cone is hypoplastic and deformed
• the squamosal bone is hypoplastic and deformed
• the styloid process is severely deformed
• at birth the mandible is markedly reduced in size
• the teeth are normal however the lower incisors are embedded in loose mesenchyme rather than the mandible
• the palatine bone is hypoplastic and deformed
• the cartilaginous rudiment of the stapes is absent in 11 out of 14 embryos
• at birth Meckel's cartilage is absent

vision/eye
• the neural crest derived melanocytes of the choroid and Harderian gland are absent

nervous system
• enteric neurons are missing from the rectum of mutants at birth
• at E12.0 enteric neurons are seen only in the proximal gut and are absent beyond the ileocecal junction

digestive/alimentary system
• at birth most of the tongue is absent
• at birth many of the submandibular and sublingual ducts are missing

hematopoietic system
• the thymus does not fully descend into the thoracic cavity


Mouse Genome Informatics
hm3
    Ece1tm1Reh/Ece1tm1Reh
involves: 129S6/SvEvTac * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• the branchial arch artery patterning abnormalities result in various types of great vessel malformations
• in E11.5 embryos 75% (6/8) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
• this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
• at E12.0 - 12.5 and E13.0 - 13.5 right arch artery 4 shows signs of regression including decreased diameter and expression of a transgenic lacZ marker of arterial smooth muscle (11 out of 13 and 5 out of 7, respectively)
• at E12.0 - 12.5 and E13.0 - 13.5 regression of left arch artery 4 is also seen but not as frequently (7 out of 13 and 4 out of 7, respectively)
• between E11.5 and E13.5 the fourth arch arteries are diminished
• in E11.5 embryos 75% (6/8) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
• this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
• at E12.0 - 12.5 in 6 out of 13 embryos right arch artery 6 abnormally persists
• at E13.0 in embryos where the right arch artery 4 regressed the right arch artery 6 persisted
• in E11.5 embryos 75% (6/8) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
• this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
• at E12.0 - 12.5 right arch artery 3 is markedly enlarged in 6 out of 13 embryos
• at E12.5 arch arteries 3 become the dominant vessels bilaterally, accepting blood from the outflow tract
• at E12.5 the overall growth of arch arteries 3 toward the cranial direction is delayed and the external carotid fails to branch off of arch arteries 3
• at E12.0 - 12.5 and E13.0 - 13.5 the right dorsal aorta remains (6 out of 13 and 6 out of 7)
• at E13.0 the connection of the right dorsal aorta to the abdominal dorsal aorta persists
• in 2 of these embryos right sided dorsal aorta is observed where left arch arteries 4 and 6 and right arch artery 4 regress, while right arch artery 6 and the right dorsal aorta persist and form the major outflow tract from the heart
• the right subclavian artery is missing or has a cervical origin in term embryos as a result of abnormal regression of right arch artery 4
• in term embryos with abnormal regression of right arch artery 4 and normal regression of the right ductus caroticus, the right dorsal aorta persists and the right subclavian artery is missing or originates from the dorsal aorta
• at E12.5 in approximately 50% of embryos both right and left ductus caroticus remain
• double aortic arch is found in term embryos when both the right and left arch arteries 4 abnormally regress or when left arch artery 6 abnormally regresses
• at E13.0 some embryos have extra branches from the ascending aorta
• other outflow tract abnormalities such as overriding aorta, double outlet right ventricle, and persistent truncus arteriosus are observed

craniofacial
• in E11.5 embryos 75% (6/8) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
• this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
• at E12.0 - 12.5 and E13.0 - 13.5 right arch artery 4 shows signs of regression including decreased diameter and expression of a transgenic lacZ marker of arterial smooth muscle (11 out of 13 and 5 out of 7, respectively)
• at E12.0 - 12.5 and E13.0 - 13.5 regression of left arch artery 4 is also seen but not as frequently (7 out of 13 and 4 out of 7, respectively)
• between E11.5 and E13.5 the fourth arch arteries are diminished
• in E11.5 embryos 75% (6/8) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
• this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
• at E12.0 - 12.5 in 6 out of 13 embryos right arch artery 6 abnormally persists
• at E13.0 in embryos where the right arch artery 4 regressed the right arch artery 6 persisted
• in E11.5 embryos 75% (6/8) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
• this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
• at E12.0 - 12.5 right arch artery 3 is markedly enlarged in 6 out of 13 embryos
• at E12.5 arch arteries 3 become the dominant vessels bilaterally, accepting blood from the outflow tract
• at E12.5 the overall growth of arch arteries 3 toward the cranial direction is delayed and the external carotid fails to branch off of arch arteries 3

embryogenesis
• in E11.5 embryos 75% (6/8) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
• this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
• at E12.0 - 12.5 and E13.0 - 13.5 right arch artery 4 shows signs of regression including decreased diameter and expression of a transgenic lacZ marker of arterial smooth muscle (11 out of 13 and 5 out of 7, respectively)
• at E12.0 - 12.5 and E13.0 - 13.5 regression of left arch artery 4 is also seen but not as frequently (7 out of 13 and 4 out of 7, respectively)
• between E11.5 and E13.5 the fourth arch arteries are diminished
• in E11.5 embryos 75% (6/8) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
• this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
• at E12.0 - 12.5 in 6 out of 13 embryos right arch artery 6 abnormally persists
• at E13.0 in embryos where the right arch artery 4 regressed the right arch artery 6 persisted
• in E11.5 embryos 75% (6/8) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
• this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
• at E12.0 - 12.5 right arch artery 3 is markedly enlarged in 6 out of 13 embryos
• at E12.5 arch arteries 3 become the dominant vessels bilaterally, accepting blood from the outflow tract
• at E12.5 the overall growth of arch arteries 3 toward the cranial direction is delayed and the external carotid fails to branch off of arch arteries 3


Mouse Genome Informatics
hm4
    Ece1tm1Reh/Ece1tm1Reh
involves: 129S6/SvEvTac * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Cardiac defects in Ece1tm1Reh/Ece1tm1Reh and Ece1tm1Reh/Ece1tm1Reh Ece2tm1Ywa/Ece2tm1Ywa embryos

cardiovascular system
• malalignment of great vessels and ventricles; the alignment between aortic and pulmonary vessel outflows remains in a spiral position as in wild-type, but the aortic valve and outflow shift rostrally and to the right so that the two valves appear in the same plane
• seen in one of ten mutants
• seen in a few mutants
• seen in many mutants
• most mutants show perimembranous ventricular septal defect

Mouse Models of Human Disease
OMIM IDRef(s)
Conotruncal Heart Malformations; CTHM 217095 J:62261


Mouse Genome Informatics
cx5
    Ece1tm1Reh/Ece1tm1Reh
Ece2tm1Ywa/Ece2tm1Ywa

involves: 129S6/SvEvTac * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Cardiac defects in Ece1tm1Reh/Ece1tm1Reh and Ece1tm1Reh/Ece1tm1Reh Ece2tm1Ywa/Ece2tm1Ywa embryos

mortality/aging
• the number of alive double homozygous mutant embryos decreased after E12.5
• the ratio of double homozygous embryos that survived until birth tended to be less than that of single Ece1 homozygous mutant embryos, but this difference did not reach statistical significance

cardiovascular system
• double homozygous mutant embryos developed cardiac abnormalities that were broader and more severe than those of single Ece1 homozygous mutant embryos
• in severe cases, the endocardial cushion was hypoplastic and did not form atrioventricular valves at all
• cardiac abnormalities included total or localized defects of the aorticopulmonary septum, which resulted in persistent truncus arteriosus or aorticopulmonary window
• seen in more than half of the mutants
• double homozygous mutant embryos displayed defects in spiraling of the conotruncal ridges and aorticopulmonary septum; these resulted in a parallel position of the aortic and pulmonary outflow tracts without crossing over each other, with the two valves observed side by side on the same transverse plane
• double homozygous mutant embryos frequently displayed abnormal atrioventricular valve formation, a phenotype never observed in single Ece1 homozygous mutant embryos
• atrioventricular valves opened toward a ventricular septal defect but not to the left ventricle

craniofacial
• near-term or E20.0 double homozygous mutant embryos had a hypoplastic mandible
• near-term or E20.0 double homozygous mutant embryos had hypoplastic pinnae

embryogenesis
N
• double E16.0-E20.0 homozygous mutant embryos displayed defects in multiple neural crest-derived tissues, which were identical to those observed in single Ece1 homozygous mutant embryos (J:62261)
• at E12.5, the endothelin-1/endothelin-2 levels in whole double homozygous mutant embryos did not differ significantly from those of single Ece1 homozygous mutant embryos (J:62261)

hearing/vestibular/ear
• near-term or E20.0 double homozygous mutant embryos had hypoplastic pinnae

skeleton
• near-term or E20.0 double homozygous mutant embryos displayed a shrunken anterior neck
• near-term or E20.0 double homozygous mutant embryos had a hypoplastic mandible

Mouse Models of Human Disease
OMIM IDRef(s)
Conotruncal Heart Malformations; CTHM 217095 J:62261


Mouse Genome Informatics
cx6
    Ece1tm1Reh/Ece1+
Ece2tm1Ywa/Ece2tm1Ywa

involves: 129S6/SvEvTac * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype
• mice heterozygous for Ece1tm1Reh and homozygous for Ece2tm1Ywa were healthy and fertile, and appeared indistinguishable from Ece1tm1Reh heterozygous mutant mice