Phenotypes associated with this allele

• Allele Symbol: Acvrl1^tm1Enl
• Allele Name: targeted mutation 1, En Li
• Allele ID: MGI:2155980
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Acvrl1^tm1Enl/Acvrl1^tm1Enl	involves: C57BL/6	MGI:3033419
ht2	Acvrl1^tm1Enl/Acvrl1^+	B6.Cg-Acvrl1^tm1Enl	MGI:5698247
ht3	Acvrl1^tm1Enl/Acvrl1^+	involves: C57BL/6	MGI:3033418
ht4	Acvrl1^tm1Spo/Acvrl1^tm1Enl	involves: 129S4/SvJae * C57BL/6	MGI:2680090

Genotype
MGI:3033419

hm1

• Allelic Composition: Acvrl1^tm1Enl/Acvrl1^tm1Enl
• Genetic Background: involves: C57BL/6

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

Abnormal yolk sac and embryo morphology of Acvrl1^tm1Enl/Acvrl1^tm1Enl mice

mortality/aging

embryonic lethality during organogenesis, complete penetrance ( J:61177 )

• homozygous mutant embryos die at midgestation and are resorbed by E11.5

cardiovascular system

abnormal blood vessel morphology ( J:61177 )

• at E9.5, very few capillary vessels are visible probably because of excessive fusion of capillary plexes (including the intersomitic arteries) into large cavernous vessels

abnormal intersomitic vessel morphology ( J:61177 )

• dilation and fusion of intersomitic vessels

abnormal angiogenesis ( J:61177 )

• vascular lesions are associated with enhanced expression of angiogenic factors and proteases

• homozygous mutant embryos exhibit defective endothelial remodeling; however vasculogenesis is normal

dilated dorsal aorta ( J:61177 )

• at E9.5, mutant embryos exhibit hyperdilation of the dorsal aorta

abnormal vitelline vasculature morphology ( J:61177 )

• at E8.5, the primary capillary plexus in the yolk sac and embryo proper appears normal

• at E9.5, the yolk sac vasculature is highly dilated, and mature blood vessels are absent

• at E10.5, the yolk sac of homozygous mutant embryos is avascular, and blood cells appear clustered

abnormal vascular smooth muscle morphology ( J:61177 )

• mutant embryos display delayed differentiation and mislocalization of vascular smooth muscle cells, resulting in failure to recruit smooth muscle cells around the arteries

arteriovenous malformation ( J:61177 )

• arteriovenous malformations involving arteriovenous shunts are evident by E8.5

dilated vasculature ( J:61177 )

• at E9.5, the lumen of major blood vessels is hyperdilated

dilated pharyngeal arch artery ( J:61177 )

• at E9.5, mutant embryos exhibit hyperdilation of the branchial arch arteries

• branchial arch arteries are greatly dilated and fused with surrounding capillaries, forming large cavernous vessels

abnormal myocardium layer morphology ( J:61177 )

• at E9.5, the mutant myocardium appears to be immature as compared to wild-type

abnormal endocardium morphology ( J:61177 )

• at E9.5, the mutant endocardium appears to be immature as compared to wild-type

enlarged pericardium ( J:61177 )

• at E10.5, mutant embryos exhibit an enlarged pericardium

craniofacial

dilated pharyngeal arch artery ( J:61177 )

• at E9.5, mutant embryos exhibit hyperdilation of the branchial arch arteries

• branchial arch arteries are greatly dilated and fused with surrounding capillaries, forming large cavernous vessels

embryo

dilated pharyngeal arch artery ( J:61177 )

• at E9.5, mutant embryos exhibit hyperdilation of the branchial arch arteries

• branchial arch arteries are greatly dilated and fused with surrounding capillaries, forming large cavernous vessels

abnormal vitelline vasculature morphology ( J:61177 )

• at E8.5, the primary capillary plexus in the yolk sac and embryo proper appears normal

• at E9.5, the yolk sac vasculature is highly dilated, and mature blood vessels are absent

• at E10.5, the yolk sac of homozygous mutant embryos is avascular, and blood cells appear clustered

embryonic growth retardation ( J:61177 )

• at E8.5, mutant embryos appear morphologically normal

• at E9.5, mutant embryos display delayed posterior development

• at E10.5, homozygous mutant embryos become severely distorted and display severe growth retardation

muscle

abnormal vascular smooth muscle morphology ( J:61177 )

• mutant embryos display delayed differentiation and mislocalization of vascular smooth muscle cells, resulting in failure to recruit smooth muscle cells around the arteries

abnormal myocardium layer morphology ( J:61177 )

• at E9.5, the mutant myocardium appears to be immature as compared to wild-type

growth/size/body

embryonic growth retardation ( J:61177 )

• at E8.5, mutant embryos appear morphologically normal

• at E9.5, mutant embryos display delayed posterior development

• at E10.5, homozygous mutant embryos become severely distorted and display severe growth retardation

microcephaly ( J:61177 )

• at E9.5, homozygous mutant embryos become readily identifiable by their smaller head size

Genotype
MGI:5698247

ht2

• Allelic Composition: Acvrl1^tm1Enl/Acvrl1⁺
• Genetic Background: B6.Cg-Acvrl1^tm1Enl

cardiovascular system

abnormal circadian regulation of systemic arterial blood pressure ( J:226550 )

♂ • mutants show alterations in arterial pressure circadian rhythm; the reduction in arterial pressure seen during the light period is less pronounced in mutants and they maintain higher arterial pressure during most of the light period

♂ • mutants have higher arterial pressure around midnight compared to wild-type mice

hypertension ( J:226550 )

♂ • mice show increased systolic and diastolic arterial pressure with normal cardiac and renal function

♂ • however, no differences in heart rate, ECG readings, and cardiac function or structure are seen

homeostasis/metabolism

increased circulating adrenaline level ( J:226550 )

♂ • plasma concentrations of epinephrine are higher

decreased circulating angiotensin II level ( J:226550 )

♂ • plasma angiotensin II levels are slightly but significantly lower

increased circulating noradrenaline level ( J:226550 )

♂ • plasma concentrations of norepinephrine are higher

abnormal enzyme/coenzyme activity ( J:226550 )

♂ • renal tissue angiotensin II-converting enzyme activity is lower

abnormal physiological response to xenobiotic ( J:226550 )

♂ • administration of captopril for 4 days decreases systolic arterial pressure to a greater extent than in wild-type mice

♂ • after i.v. angiotensin II administration, the increase in arterial pressure measured by direct cannulation of the carotid artery in anesthetized mice is lower in mutants than in wild-type mice, however the change in vascular resistance in response to angiotensin II is not different

♂ • the contractile response of aortic rings to increasing doses of phenylephrine is lower in mutants than in wild-type mice, even when corrected by KCl-induced contraction

♂ • mutants are more sensitive to the hypotensive effects of intracerebroventricular losartan and less sensitive to the hypertensive effects of intracerebroventricular angiotensin II

nervous system

dilated brain ventricle ( J:226550 )

♂ • some mice show ventricular dilatation

abnormal cholinergic neuron morphology ( J:226550 )

♂ • reduction in the numbers of cholinergic neurons in the anterior basal forebrain

abnormal sympathetic nervous system physiology ( J:226550 )

♂ • hypotensive response to acute administration of a beta-adrenergic receptor antagonist atenolol is greater in mutants than in wild-type mice, however the hypotensive response to acute administration of the alpha-adrenergic receptor antagonist prazosin is similar to wild-type mice, indicating sympathetic nervous system overactivation

renal/urinary system

renal/urinary system phenotype ( J:226550 )

♂N • plasma creatinine levels, creatinine clearance, urinary protein excretion, urinary sodium excretion, and kidney morphology appear normal

Genotype
MGI:3033418

ht3

• Allelic Composition: Acvrl1^tm1Enl/Acvrl1⁺
• Genetic Background: involves: C57BL/6

mortality/aging

premature death ( J:82115 )

• when allowed to live beyond 1 year of age, some heterozygotes die spontaneously, or are euthanized due to morbidity

cardiovascular system

cardiovascular system phenotype ( J:82115 )

N • at the age of >1 year, heterozygotes develop an age-dependent hereditary hemorrhagic telangiectasia (HHT)-like phenotype

dilated liver sinusoidal space ( J:82115 )

• sinusoidal capillaries are grossly dilated in affected liver lobes

hemorrhage ( J:82115 )

• the first and most frequently observed external manifestation of vascular pathology is the presence of discolored, cyanotic nailbeds and hemorrhage into claws

• histological examination of affected nailbeds revealed numerous closely packed telangiectases altering the adjacent bone

gastrointestinal hemorrhage ( J:82115 )

• some heterozygous mutants show visible gastrointestinal bleeding, as well as positive fecal occult blood tests

telangiectasia ( J:82115 )

• heterozygotes display vascular lesions (telangiectases) consisting of hyperdilated vessels with normal or thin walls, in isolation or in clusters, in normal or abnormal locations

• vascular lesions are observed in the skin, oral cavity, liver, spleen, lung, intestine and brain

• vascular lesions are often associated with hemorrhage, organ enlargement and/or fibrosis

• at least one vascular lesion is observed in ~40% of heterozygous mutant mice of a predominately C57BL/6 genetic background by the age of 12 months or older

digestive/alimentary system

gastrointestinal hemorrhage ( J:82115 )

• some heterozygous mutants show visible gastrointestinal bleeding, as well as positive fecal occult blood tests

liver/biliary system

abnormal hepatobiliary system morphology ( J:82115 )

• the range of gross liver lesions include focal lesions that are ~1-2 mm in diameter and consist of multiple thin-walled vessels that are hyperdilated and juxtaposed to each other

• liver lesions are the most predominant among vascular defects, and are associated with chronic hemorrhage, fibrosis, and morbidity

• one heterozygous mutant mouse with severe liver pathology, including hepatic arteriovenous malformations, also displayed a secondary cardiac phenotype, comprising of myocardial ischemia and loss

dilated liver sinusoidal space ( J:82115 )

• sinusoidal capillaries are grossly dilated in affected liver lobes

enlarged liver ( J:82115 )

muscle

telangiectasia ( J:82115 )

• heterozygotes display vascular lesions (telangiectases) consisting of hyperdilated vessels with normal or thin walls, in isolation or in clusters, in normal or abnormal locations

• vascular lesions are observed in the skin, oral cavity, liver, spleen, lung, intestine and brain

• vascular lesions are often associated with hemorrhage, organ enlargement and/or fibrosis

• at least one vascular lesion is observed in ~40% of heterozygous mutant mice of a predominately C57BL/6 genetic background by the age of 12 months or older

growth/size/body

enlarged liver ( J:82115 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hereditary hemorrhagic telangiectasia		DOID:1270	OMIM:187300 OMIM:600376 OMIM:601101 OMIM:615506	J:82115

Genotype
MGI:2680090

ht4

• Allelic Composition: Acvrl1^tm1Spo/Acvrl1^tm1Enl
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

embryonic lethality during organogenesis, complete penetrance ( J:85877 )

• heterozygotes die around E9.5-E10.5

cardiovascular system

abnormal vascular development ( J:85877 )

• severe vascular defects at E9.5-E10.5 when heterozygotes die