Phenotypes associated with this allele

• Allele Symbol: Mb^tm1Wlm
• Allele Name: targeted mutation 1, R Saunders Williams
• Allele ID: MGI:2159349
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Mb^tm1Wlm/Mb^tm1Wlm	B6.Cg-Mb^tm1Wlm	MGI:3573777
hm2	Mb^tm1Wlm/Mb^tm1Wlm	either: (involves: 129/Sv) or (involves: C57BL/6)	MGI:3573775
hm3	Mb^tm1Wlm/Mb^tm1Wlm	Not Specified	MGI:3531103
ht4	Mb^tm1Wlm/Mb^+	either: (involves: 129/Sv) or (involves: C57BL/6)	MGI:3573776

Genotype
MGI:3573777

hm1

• Allelic Composition: Mb^tm1Wlm/Mb^tm1Wlm
• Genetic Background: B6.Cg-Mb^tm1Wlm

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

cardiovascular system

heart left ventricle hypertrophy ( J:86546 )

• in response to chronic hypoxia (10% oxygen for 1 day to 3 wk), male homozygotes display a similar degree of RT and LV hypertrophy (and LV wall thickness) relative to wild-type males

• no ischemic or necrotic myocardial injury is observed under hypoxic conditions

decreased ventricle muscle contractility ( J:86546 )

• in response to chronic hypoxia (10% oxygen for 1 day to 3 wk), male homozygotes display a 30% reduction in cardiac systolic function; no changes in heart rate are observed relative to wild-type mice

• this degree of hypoxia-induced LV systolic dysfunction remains constant, regardless of the period of hypoxic exposure (1?3 wk)

• hypoxia-induced cardiac dysfunction is reversible upon reexposure to normoxic conditions (21% O2) and can be prevented with treatment of an inhibitor of nitric oxide (NO) synthases

homeostasis/metabolism

abnormal nitric oxide homeostasis ( J:86546 )

• homozygous mutant males show perturbed nitric oxide (NO) homeostasis

• in response to chronic hypoxia, mutant males exhibit a significant induction of inducible NO synthase (iNOS) activity in the left ventricles, in the absence of appreciable differences in cGMP levels relative to wild-type males

hypoxia ( J:86546 )

• in response to chronic hypoxia (10% oxygen for 1 day to 3 wk), male homozygotes show a similar rise in serum hematocrit levels relative to wild-type males, indicating a normal serum oxygen-carrying capacity

• in addition, both hypoxic wild-type and mutant males show a finite (~35%) increase in capillary density of the LV

muscle

heart left ventricle hypertrophy ( J:86546 )

• in response to chronic hypoxia (10% oxygen for 1 day to 3 wk), male homozygotes display a similar degree of RT and LV hypertrophy (and LV wall thickness) relative to wild-type males

• no ischemic or necrotic myocardial injury is observed under hypoxic conditions

decreased ventricle muscle contractility ( J:86546 )

• in response to chronic hypoxia (10% oxygen for 1 day to 3 wk), male homozygotes display a 30% reduction in cardiac systolic function; no changes in heart rate are observed relative to wild-type mice

• this degree of hypoxia-induced LV systolic dysfunction remains constant, regardless of the period of hypoxic exposure (1?3 wk)

• hypoxia-induced cardiac dysfunction is reversible upon reexposure to normoxic conditions (21% O2) and can be prevented with treatment of an inhibitor of nitric oxide (NO) synthases

growth/size/body

heart left ventricle hypertrophy ( J:86546 )

• in response to chronic hypoxia (10% oxygen for 1 day to 3 wk), male homozygotes display a similar degree of RT and LV hypertrophy (and LV wall thickness) relative to wild-type males

• no ischemic or necrotic myocardial injury is observed under hypoxic conditions

Genotype
MGI:3573775

hm2

• Allelic Composition: Mb^tm1Wlm/Mb^tm1Wlm
• Genetic Background: either: (involves: 129/Sv) or (involves: C57BL/6)

mortality/aging

embryonic lethality during organogenesis, incomplete penetrance ( J:74121 )

• at E8.0-E9.0, all homozygous mutant embryos are viable and appear grossly normal

• at E9.5-E10.5, many homozygous mutants are phenotypically abnormal or dead with no signs of resorption

• at E11-E112.5, all of the viable homozygotes appear grossly normal

cardiovascular system

cardiovascular system phenotype ( J:74121 )

N • adult homozygotes exhibit normal cardiac output, stroke volume, heart rate, and coronary flow relative to wild-type mice

N • substrate utilization is relatively preserved with fatty acids being the major metabolic substrate; a modest increase in lactate utilization is noted in mutant hearts

N • despite a 20% increase in heart rate, mutant hearts show no differences in myocardial oxygen consumption in response to short-term adrenergic (isoproterenol) stimulation

N • furthermore, homozygotes survive ischemic injury and suffer a left ventricular dysfunction comparable to that of wild-type mice when exposed to the same coronary ligation protocol

abnormal vasculogenesis ( J:74121 )

• at E12.5, hearts of surviving mutant embryos exhibit hypervascularity relative to wild-type hearts

• at E12.5 and E13.5, mutant survivors display a 48% increase in capillary density of the ventricles and ventricular septum relative to wild-type embryo

• in adults, quantitation of capillaries indicates a significant increase in vascular supply in the atria (46%) and ventricles (28%) of mutant hearts

thin myocardium ( J:74121 )

• at E9.5-E10.5, runted homozygous mutant embryos exhibit a thin myocardium in the absence of increased apoptosis

abnormal fetal cardiomyocyte morphology ( J:74121 )

• at E10.5, abnormal but viable mutant hearts show an underdeveloped sarcomeric myosin actin contractile apparatus relative to wild-type hearts

cardiac hypertrophy ( J:74121 )

• homozygotes develop cardiac hypertrophy, induced by long-term beta-adrenergic stimulation, in the absence of overt hemodynamic alterations

pericardial effusion ( J:74121 )

• at E9.5-E10.5, 4 out of 12 homozygous mutant embryos exhibit pericardial effusion consistent with congestive heart failure

hemorrhage ( J:74121 )

• at E9.5-E10.5, 8 out of 12 homozygous mutant embryos show diffuse hemorrhages, indicating vascular insufficiency

congestive heart failure ( J:74121 )

• at E9.5-E10.5, 4 out of 12 homozygous mutant embryos exhibit congestive heart failure

cellular

cellular phenotype ( J:74121 )

N • adult mutant hearts show no significant qualitative differences in mitochondrial content relative to wild-type hearts

embryo

embryo phenotype ( J:74121 )

N • homozygotes surviving past E11.0 show no evidence of further fetal loss or structural abnormalities relative to wild-type embryos

embryonic growth retardation ( J:74121 )

• at E9.5-E10.5, most homozygous mutant embryos display a generalized developmental delay relative to wild-type embryos

decreased embryo size ( J:74121 )

• at E9.5-E10.5, most homozygous mutant embryos display a reduced size relative to wild-type embryos

growth/size/body

cardiac hypertrophy ( J:74121 )

• homozygotes develop cardiac hypertrophy, induced by long-term beta-adrenergic stimulation, in the absence of overt hemodynamic alterations

embryonic growth retardation ( J:74121 )

• at E9.5-E10.5, most homozygous mutant embryos display a generalized developmental delay relative to wild-type embryos

decreased embryo size ( J:74121 )

• at E9.5-E10.5, most homozygous mutant embryos display a reduced size relative to wild-type embryos

hematopoietic system

hematopoietic system phenotype ( J:74121 )

N • adult homozygotes show no significant differences in hemoglobin concentration or hematocrit relative to wild-type mice

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:74121 )

N • adult homozygotes show no significant differences in the profile of serum electrolytes relative to wild-type mice

pericardial effusion ( J:74121 )

• at E9.5-E10.5, 4 out of 12 homozygous mutant embryos exhibit pericardial effusion consistent with congestive heart failure

edema ( J:74121 )

• at E10.5, abnormal but viable mutant hearts contain edematous cells in the endocardial and myocardial layers, as well as increased cytoplasmic vacuoles

• absence of apoptosis in the hearts of failing embryos is consistent with an oncotic (edema-induced) embryonic demise

hypoxia ( J:74121 )

• in response to cardiac hypoxia, ventricles from E12.5 homozygotes display enhanced expression of hypoxia-inducible factors, stress proteins (heat shock proteins), and VEGF

• such changes presumably drive cellular adaptations (e.g. increased vascularization) that preserve cardiac function when myoglobin is absent

muscle

thin myocardium ( J:74121 )

• at E9.5-E10.5, runted homozygous mutant embryos exhibit a thin myocardium in the absence of increased apoptosis

Genotype
MGI:3531103

hm3

• Allelic Composition: Mb^tm1Wlm/Mb^tm1Wlm
• Genetic Background: Not Specified

cardiovascular system

cardiovascular system phenotype ( J:50584 )

N • homozygotes exhibit normal intrinsic heart rates (<5% difference) and normal cardiac muscle histology relative to wild-type mice

N • in homozygotes, no overt signs of congestive heart failure are observed up to 10 months of age

N • in mutants, stroke work at a constant perfusing pressure (80 cm H20) increases normally in response to changes in preload

increased angiogenesis ( J:72560 )

• homozygotes exhibit increased vasculogenesis in slow-twitch oxidative soleus muscles, as shown by a 21% increase in capillary density relative to wild-type mice

• no differences in capillary density are observed in fast-twitch EDL muscles

abnormal myocardium layer morphology ( J:50584 )

• mutant perfused heart muscles display depigmentation relative to wild-type muscles

cellular

cellular phenotype ( J:72560 )

N • adult homozygotes show no significant structural abnormalities in mitochondria or qualitative differences in mitochondrial content of soleus muscles relative to wild-type mice

growth/size/body

growth/size/body region phenotype ( J:50584 )

N • homozygotes are viable and fertile and gain weight at a rate that is comparable to those of wild-type mice

homeostasis/metabolism

hypoxia ( J:72560 )

• in response to tissue hypoxia, soleus muscles from adult mutant mice display enhanced expression of hypoxia-inducible factors, stress proteins, and VEGF; similar molecular profiles (excluding VEGF) are noted in mutant EDL muscles

abnormal metabolism ( J:72560 )

• following electrical stimulation, mutant EDL muscles exhibit increased nitric oxide (NO) metabolism (a 2.1-fold increase in cGMP formation) relative to wild-type EDL muscles

• in mutant EDS muscles, this increase is presumed to promote oxygen delivery by a NO-mediated vasodilation mechanism and is shown to be attenuated by a nitric oxide synthase inhibitor

• no significant increase in cGMP is observed between stimulated wild-type and mutant soleus muscles

muscle

muscle phenotype ( J:50584 )

N • homozygotes exhibit no differences in skeletal muscle histology relative to wild-type mice

N • in vitro, isolated cardiac and skeletal muscles show normal muscle performance across a range of work conditions and oxygen availability

N • isolated soleus and extensor digitorum longus muscles show normal twitch properties and fatigue at a normal rate in response to intermittent tetani under both well-oxygenated and hypoxic conditions

abnormal myocardium layer morphology ( J:50584 )

• mutant perfused heart muscles display depigmentation relative to wild-type muscles

abnormal soleus morphology ( J:50584 , J:72560 )

• mutant perfused soleus muscles display depigmentation relative to wild-type muscles (J:50584)

• in mutant soleus muscles, slow (type I) myofibers are decreased, whereas fast (type II) myofibers are increased relative to wild-type (J:72560)

• mutant soleus muscles display a 21% increase in capillary density relative to wild-type muscles (J:72560)

abnormal skeletal muscle fiber type ratio ( J:72560 )

• homozygotes exhibit adaptations in skeletal muscle including a fiber type transition from oxidative type I (slow) to oxidative type IIa (fast) in soleus muscle

increased muscle fatigability ( J:72560 )

• in soleus muscles (i.e. slow-twitch fibers), fiber type transition is paralleled by changes in physiological variables: low-frequency fatigue is observed only in mutant (but not in wild-type) soleus muscles

• in extensor digitorum longus (EDL) muscles (i.e. fast-twitch fibers), low-frequency fatigue is noted in both genotypes

respiratory system

respiratory system phenotype ( J:50584 )

N • homozygotes exhibit normal exercise performance at intensities that require high rates of oxygen flux

N • in addition, homozygotes survive exposure to a hypoxic gas mixture (13.5% oxygen), and display normal ventilatory responses during and following the period of reduced inspiratory oxygen tension

limbs/digits/tail

abnormal soleus morphology ( J:50584 , J:72560 )

• mutant perfused soleus muscles display depigmentation relative to wild-type muscles (J:50584)

• in mutant soleus muscles, slow (type I) myofibers are decreased, whereas fast (type II) myofibers are increased relative to wild-type (J:72560)

• mutant soleus muscles display a 21% increase in capillary density relative to wild-type muscles (J:72560)

Genotype
MGI:3573776

ht4

• Allelic Composition: Mb^tm1Wlm/Mb⁺
• Genetic Background: either: (involves: 129/Sv) or (involves: C57BL/6)

mortality/aging

embryonic lethality during organogenesis, incomplete penetrance ( J:74121 )

• at E8.0-E9.0, all heterozygous mutant embryos are viable and appear grossly normal

• at E9.5-E10.5, many heterozygous mutants are phenotypically abnormal or dead with no signs of resorption

• at E11-E112.5, all of the viable heterozygotes appear grossly normal

cardiovascular system

pericardial effusion ( J:74121 )

• at E9.5-E10.5, only a few heterozygotes exhibit pericardial effusion

hemorrhage ( J:74121 )

• at E9.5-E10.5, only a few heterozygotes show diffuse hemorrhages, indicating vascular insufficiency

congestive heart failure ( J:74121 )

• at E9.5-E10.5, only a few heterozygotes exhibit congestive heart failure

embryo

embryonic growth retardation ( J:74121 )

• at E9.5-E10.5, only a few heterozygotes display a generalized developmental delay relative to wild-type embryos

decreased embryo size ( J:74121 )

• at E9.5-E10.5, only a few heterozygotes display a reduced size relative to wild-type embryos

growth/size/body

embryonic growth retardation ( J:74121 )

• at E9.5-E10.5, only a few heterozygotes display a generalized developmental delay relative to wild-type embryos

decreased embryo size ( J:74121 )

• at E9.5-E10.5, only a few heterozygotes display a reduced size relative to wild-type embryos

homeostasis/metabolism

pericardial effusion ( J:74121 )

• at E9.5-E10.5, only a few heterozygotes exhibit pericardial effusion