Mouse Genome Informatics
hm1
    Plautm1Mlg/Plautm1Mlg
B6.129S2-Plautm1Mlg
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• only 5 of 8 mice survive for a year

immune system
• chronic inflammation is secondary to fibrin deposition
• in the liver and trachea
• however, leukocyte accumulation in standard models of inflammation is normal
• the number of inflammatory foci is increased compared to in wild-type mice

liver/biliary system
• 2.5-fold more frequent in number compared with Plautm1.1Bug or Plaurtm1Jld homozygotes
• the number of inflammatory foci is increased compared to in wild-type mice

homeostasis/metabolism
• following treatment with carbon tetrachloride, substantial areas of necrosis persist in the liver unlike in similarly treated wild-type mice
• however, skin wound healing is normal
• 2.5-fold more frequent in number compared with Plautm1.1Bug or Plaurtm1Jld homozygotes

respiratory system
• all mice exhibit inflammation in the tracheal with basement membrane hyperplasia and desquamation of the tracheal epithelium unlike in wild-type mice
• mice exhibit fibrosis in the trachea unlike wild-type mice

adipose tissue

growth/size
• some mice die before 1 year with a wasting syndrome


Mouse Genome Informatics
hm2
    Plautm1Mlg/Plautm1Mlg
B6.Cg-Plautm1Mlg
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• following implantation of T241 fibrosarcoma cells, only a limited number of mutants develop metastatic lesions in the lung and brain; in contrast, almost all of wild-type mice display metastases to the same locations
• notably, only mutants that survive for longer periods (2 months) after the injection develop these lesions, indicating a delay in metastasis
• 3 weeks after implantation of T241 fibrosarcoma cells, primary tumors from mutant mice appear to be better delineated and less hemorrhagic than tumors from wild-type mice
• also, tumors from mutant mice show an increase in collagen deposition at the periphery of the lesion, forming a fibrous and thick pseudocapsule that is almost undetectable in tumors from wild-type mice
• ultrastructurally, fibrosarcoma tumor neovessels formed in mutant mice are larger and less mature than tumor vessels from wild-type mice
• 3 weeks after implantation of T241 fibrosarcoma cells, primary tumors from mutant mice are significantly smaller than tumors from wild-type mice
• consistent with tumor growth suppression, tumor tissues from mutant mice exhibit lower proliferative and higher apoptotic indices relative to tumor tissues from wild-type mice

digestive/alimentary system
• in males with rectal prolapse, the rectal mucosa is exteriorized and evaginated
• starting at 6 months, male (but not female) homozygotes show a high incidence of rectal prolapse
• in mutant males, rectal prolapse is irreducible and completely exteriorized by 12 months
• in males with rectal prolapse, the perineal region is swollen on both sides of the evaginated rectal mucosa

endocrine/exocrine glands
• males with rectal prolapse develop an irreducible hernia of the seminal vesicles through the pelvic outlet and through a hiatus found between the iliococcygeus (ISC), the bulbocavrnosus (BC), and the tail (J:73613)
• this hernia results in chronic stretching and thinning of the ISC, BC, and levator ani (LA) pelvic floor muscles (J:73613)

immune system
• in response to skeletal muscle degeneration, homozygotes display a 50% reduction in macrophage recruitment at the injury site 48 hours after glycerol-induced injury
• despite a normal antibody response to type II collagen, T cells from arthritic homozygotes show a reduced proliferative response and produce less interferon-gamma on antigen stimulation in vitro
• at 9 days after glycerol-induced injury of skeletal muscles, homozygotes exhibit abundant fibrin deposits in degenerating muscle fibers
• in a model of collagen-induced arthritis, arthritic homozygotes exhibit a significant reduction in interleukin-1beta levels in the synovium relative to wild-type
• in a model of collagen-induced arthritis, arthritic homozygotes exhibit a significant reduction in TNF levels in the synovium relative to wild-type
• in a model of collagen-induced arthritis, homozygotes develop a significantly milder disease than wild-type mice, with little inflammation and joint destruction
• in this chronic systemic model, the affected limbs of mutants are rigid but not swollen; arthritis is largely confined to the ankle joint, with most joints in the feet appearing normal
• surprisingly, the joints of arthritic homozygotes display minimal fibrin(ogen) deposition relative to wild-type
• in response to glycerol-induced muscle degeneration, homozygotes display significantly reduced numbers of macrophages and neutrophils at the site of injury relative to wild-type

muscle
• in response to glycerol-induced injury, homozygotes exhibit a severe skeletal muscle regeneration defect relative to wild-type; this defect is apparent at 5 days but is most striking at 9 and 20 days after injury
• at 5 days after injury, skeletal muscles from mutant mice appear edematous; in contrast to wild-type, no uninucleated, small myofibers are yet formed
• at 7 days after injury, most injured skeletal muscles appear necrotic and show extensive fibrosis
• at 9 and 20 days, numerous degenerated myotubes and fibrosis are still visible in mutant muscles whereas no signs of previous damage are detectable in wild-type muscles
• systemic fibrinogen depletion via ancrod administration restores muscle regeneration: 9 days after injury, ancrod-treated mutants exhibit improved muscle regeneration, with centrally located nuclei inside the regenerated fibers
• males with rectal prolapse, exhibit myopathic damage in the affected pelvic floor muscles (ISC, BC and LA)
• most affected myofibers have centrally located nuclei; some show basophilic degeneration in the absence of denervation, fibrosis or inflammation

reproductive system
• in males with rectal prolapse, the perineal region is swollen on both sides of the evaginated rectal mucosa
• males with rectal prolapse develop an irreducible hernia of the seminal vesicles through the pelvic outlet and through a hiatus found between the iliococcygeus (ISC), the bulbocavrnosus (BC), and the tail (J:73613)
• this hernia results in chronic stretching and thinning of the ISC, BC, and levator ani (LA) pelvic floor muscles (J:73613)

skeleton
• in a model of collagen-induced arthritis, homozygotes develop a significantly milder disease than wild-type mice, with little inflammation and joint destruction
• in this chronic systemic model, the affected limbs of mutants are rigid but not swollen; arthritis is largely confined to the ankle joint, with most joints in the feet appearing normal
• surprisingly, the joints of arthritic homozygotes display minimal fibrin(ogen) deposition relative to wild-type

homeostasis/metabolism
• at 9 days after glycerol-induced injury of skeletal muscles, homozygotes exhibit abundant fibrin deposits in degenerating muscle fibers
• in a model of collagen-induced arthritis, arthritic homozygotes exhibit a significant reduction in interleukin-1beta levels in the synovium relative to wild-type
• in a model of collagen-induced arthritis, arthritic homozygotes exhibit a significant reduction in TNF levels in the synovium relative to wild-type

hematopoietic system
• in response to skeletal muscle degeneration, homozygotes display a 50% reduction in macrophage recruitment at the injury site 48 hours after glycerol-induced injury
• despite a normal antibody response to type II collagen, T cells from arthritic homozygotes show a reduced proliferative response and produce less interferon-gamma on antigen stimulation in vitro

cellular
• in response to skeletal muscle degeneration, homozygotes display a 50% reduction in macrophage recruitment at the injury site 48 hours after glycerol-induced injury


Mouse Genome Informatics
hm3
    Plautm1Mlg/Plautm1Mlg
either: B6.Cg-Plautm1Mlg or (involves: Black Swiss * C57BL/6)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• in a model of pulmonary microembolism, wild-type mice are able to clear 125I-microemboli rapidly with complete lysis by 5 hours; in contrast, mutants remain unable to lyse pulmonary microemboli throughout the 5-hr experimental period
• in these mutants, impaired fibrinolysis can be rescued completely by providing urokinase exogenously


Mouse Genome Informatics
hm4
    Plautm1Mlg/Plautm1Mlg
involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• homozygotes display a normal lifespan relative to wild-type mice (J:17427)

growth/size
N
• at 5 weeks of age, homozygotes exhibit a normal body weight relative to wild-type mice (J:17427)
• at ~26 weeks of age, 5% of homozygotes display severe non-healing ulcerations at the ears around the ear tag and the face

cardiovascular system
• in response to laser-induced injury of the Bruch's membrane, homozygotes display almost complete absence of choroidal neovascularization (CNV) at the site of trauma; in contrast, wild-type mice show a robust neovascular reaction
• resistance to CNV is associated with excessive fibrinogen-fibrin deposition at the site of choroidal trauma and in retinal vessels
• after transverse aortic banding (TAB), i.e. acute pressure overload, homozygotes remain significantly protected against LV hypertrophy for at least 7 weeks
• homozygotes display only a 20% increase in LV/body ratio and only a 22% increase in LV cardiomyocyte size relative to wild-type (~35% and ~40%, respectively)
• at 7 weeks after TAB, LV systolic dysfunction and dilatation are only marginally detectable without signs of pulmonary edema
• in response to pressure overload, homozygotes show only minimal signs of maladaptation (i.e. myolysis, fibrosis or increased intercapillary distance) relative to wild-type mice
• at 7 weeks after TAB, homozygotes exhibit increased LV contractility, indicating normal fractional shortening with no cardiac failure or pulmonary congestion

digestive/alimentary system
• at ~22 weeks of age, 9% of homozygotes display rectal prolapse of a non-infectious origin

hearing/vestibular/ear
• at ~26 weeks of age, 5% of homozygotes display severe non-healing ulcerations at the ears around the ear tag and the face

hematopoietic system
N
• homozygotes exhibit normal spontaneous lysis of a 125I-fibrin-labeled pulmonary plasma clot relative to wild-type (J:17427)
• at day 7 post-treatment, the decline in macrophage counts coincides with an increase in the percentage of lymphocytes found in the lungs of bleomycin-treated mice
• 48 hours after intranasal inoculation with S. pneumoniae, homozygotes exhibit an enhanced antibacterial host defense, with less pneumococci in their lungs and increased neutrophil influx in the bronchoalveolar lavage fluid but no reduction in mortality relative to wild-type (J:75573)
• relative to wild-type, purified neutrophils from mutant mice exhibit a ~50% reduction in superoxide production in response to fMLP (a potent chemotaxin and activator of neutrophils) across the entire dose range tested; repletion with murine uPA completely reverses the defect in superoxide generation (J:91980)
• in response to fMLP, mutant neutrophils exhibit reduced neutrophil exocytosis of azurophilic granules (as shown by reduced myeloperoxidase release); however, this defect is not corrected by repletion with extracellular uPA (J:91980)
• in contrast, mutant neutrophils show normal agonist-stimulated release of specific granules relative to wild-type neutrophils (J:91980)
• in vitro, purified neutrophils from mutant mice exhibit a significant reduction in phagocytosis of E. coli at all time points; repletion with murine uPA substantially reverses the defect in neutrophil phagocytosis
• in vitro, purified neutrophils from mutant mice display significant defects in several aspects of the antibacterial neutrophil activation process that lead to E. coli killing and effective host defense
• in contrast to wild-type, homozygotes exhibit no plasminogen-dependent breakdown of 125I-fibrin-labeled matrix and of 3H-proline-labeled subendothelial breakdown by thioglycollate-activated macrohages; invasion of macrophages into the peritoneal cavity remains unaffected
• 5 days after bleomycin treatment, homozygotes display a peak in lung macrophage levels that coincides with the peak time observed in wild-type mice; however, their marcophage levels are significantly reduced relative to wild-type
• 7 days after bleomycin treatment, mutant and wild-type mice show a similar decrease in the number and percentage of macrophages found in the lung

immune system
• at day 7 post-treatment, the decline in macrophage counts coincides with an increase in the percentage of lymphocytes found in the lungs of bleomycin-treated mice
• bleomycin-treated homozygotes exhibit extensive areas of fibrin(ogen) deposition in the lung interstitium which are associated with areas of fibrosis (J:63134)
• after laser-induced injury of the Bruch's membrane, homozygotes show massive accumulation of fibrinogen-fibrin both in the retinal vessels, and in the bottom of the laser-induced trauma (J:82604)
• homozygotes fail to generate a type 2 immune response following schistosomal antigen challenge (J:87817)
• in response to schistosomal egg antigen (SEA), homozygotes fail to develop a delayed-type hypersensitivity response to SEA, do not polarize Ig production to IgE, fail to produce high levels of IL-4, IL-5, or IL-13 and generate pulmonary granulomas that are deficient in eosinophils (J:87817)
• homozygotes fail to generate a type 1 immune response in the lung during pulmonary fungal infection with C. neoformans (J:95638)
• in response to C. neoformans infection, homozygotes show impaired T cell proliferation in regional lymph nodes and fail to produce high levels of T1 cytokines (IFN-gamma and IL-12) in the lung; instead, mutants exhibit increased levels of IL-5, a T2 cytokine (J:95638)
• 48 hours after intranasal inoculation with S. pneumoniae, homozygotes exhibit an enhanced antibacterial host defense, with less pneumococci in their lungs and increased neutrophil influx in the bronchoalveolar lavage fluid but no reduction in mortality relative to wild-type (J:75573)
• relative to wild-type, purified neutrophils from mutant mice exhibit a ~50% reduction in superoxide production in response to fMLP (a potent chemotaxin and activator of neutrophils) across the entire dose range tested; repletion with murine uPA completely reverses the defect in superoxide generation (J:91980)
• in response to fMLP, mutant neutrophils exhibit reduced neutrophil exocytosis of azurophilic granules (as shown by reduced myeloperoxidase release); however, this defect is not corrected by repletion with extracellular uPA (J:91980)
• in contrast, mutant neutrophils show normal agonist-stimulated release of specific granules relative to wild-type neutrophils (J:91980)
• in vitro, purified neutrophils from mutant mice exhibit a significant reduction in phagocytosis of E. coli at all time points; repletion with murine uPA substantially reverses the defect in neutrophil phagocytosis
• in vitro, purified neutrophils from mutant mice display significant defects in several aspects of the antibacterial neutrophil activation process that lead to E. coli killing and effective host defense
• in contrast to wild-type, homozygotes exhibit no plasminogen-dependent breakdown of 125I-fibrin-labeled matrix and of 3H-proline-labeled subendothelial breakdown by thioglycollate-activated macrohages; invasion of macrophages into the peritoneal cavity remains unaffected
• 5 days after bleomycin treatment, homozygotes display a peak in lung macrophage levels that coincides with the peak time observed in wild-type mice; however, their marcophage levels are significantly reduced relative to wild-type
• 7 days after bleomycin treatment, mutant and wild-type mice show a similar decrease in the number and percentage of macrophages found in the lung
• 21 days after inoculation with Cryptococcus neoformans, homozygotes contain significantly higher lung CFUs than wild-type mice
• C. neoformans-infected mutants disseminate the fungal pathogen to their spleen; eventually 15 out of 19 mutants (versus 3/19 wild-type) die from fungal meningitis
• when primed homozygotes are challenged with schistosomal egg antigen (SEA) they exhibit a severe immune defect in response to this T2-eliciting antigen

muscle
• at 7 weeks after TAB, homozygotes exhibit increased LV contractility, indicating normal fractional shortening with no cardiac failure or pulmonary congestion

reproductive system
N
• homozygotes display normal litter size and frequency of litters relative to wild-type mice (J:17427)

respiratory system
• 14 days after bleomycin treatment, homozygotes exhibit an increase in lung hydroxyproline (collagen) content that is comparable to that observed in bleomycin-treated wild-type mice
• histological analysis 14 days after lung injury indicates extensive interstitial fibrosis in mutant mice relative to wild-type; however, no hemorrhage or extensive collagen deposition is observed
• 62% of bleomycin-treated homozygotes die as early as ~7 days after treatment, possibly as a result of extensive fibrosis

vision/eye
• in response to laser-induced injury of the Bruch's membrane, homozygotes display almost complete absence of choroidal neovascularization (CNV) at the site of trauma; in contrast, wild-type mice show a robust neovascular reaction
• resistance to CNV is associated with excessive fibrinogen-fibrin deposition at the site of choroidal trauma and in retinal vessels
• at ~26 weeks of age, 5% homozygotes display severe non-healing ulcerations at the eyelids

nervous system
N
• homozygotes subjected to focal cerebral ischemia induced by persistent occlusion of the left middle cerebral artery produce an infarct with a size that is comparable to that produced in wild-type mice (J:55243)
• Abeta40 and 42 levels are not increased in mutant brains relative to controls (J:104962)

homeostasis/metabolism
• in response to pressure overload, homozygotes show only minimal signs of maladaptation (i.e. myolysis, fibrosis or increased intercapillary distance) relative to wild-type mice
• 3-6 month-old mice have elevated levels of plasma amyloid beta 42 (Abeta42) and Abeta40; by 11 months of age, difference in levels between mutants and controls has increased significantly
• homozygotes occasionally exhibit small, focal fibrin deposits in the intestines and in the sinusoids of the liver and extensive fibrin deposits in the ulcerated skin, ear or prolapsed rectum
• in response to injection of pro-inflammatory endotoxin in the footpad, homozygotes exhibit overt venous thrombosis at a significantly higher incidence (90% versus 54%) and to a much larger extent than wild-type mice (60% of mutants show >4 thrombosed veins per tissue section versus only 15% in wild-type)
• bleomycin-treated homozygotes exhibit extensive areas of fibrin(ogen) deposition in the lung interstitium which are associated with areas of fibrosis (J:63134)
• after laser-induced injury of the Bruch's membrane, homozygotes show massive accumulation of fibrinogen-fibrin both in the retinal vessels, and in the bottom of the laser-induced trauma (J:82604)
• 14 days after bleomycin treatment, homozygotes exhibit an increase in lung hydroxyproline (collagen) content that is comparable to that observed in bleomycin-treated wild-type mice
• histological analysis 14 days after lung injury indicates extensive interstitial fibrosis in mutant mice relative to wild-type; however, no hemorrhage or extensive collagen deposition is observed
• 62% of bleomycin-treated homozygotes die as early as ~7 days after treatment, possibly as a result of extensive fibrosis

craniofacial
• at ~26 weeks of age, 5% of homozygotes display severe non-healing ulcerations at the ears around the ear tag and the face

cellular
• 5 days after bleomycin treatment, homozygotes display a peak in lung macrophage levels that coincides with the peak time observed in wild-type mice; however, their marcophage levels are significantly reduced relative to wild-type
• 7 days after bleomycin treatment, mutant and wild-type mice show a similar decrease in the number and percentage of macrophages found in the lung

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:104962


Mouse Genome Informatics
cx5
    Apoetm1Bres/Apoetm1Bres
Plautm1Mlg/Plautm1Mlg

involves: 129 * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• at >15 weeks of age, double homozygotes fed an atherogenic diet display minimal fragmentation of the internal elastic membranes (EMs) in 10% of plaques; in contrast, Apoetm1Bres mice show fragmentation of EMs in 51% of plaques, and perforating transmedial ulceration in 21% of plaques
• at >15 weeks of age, double homozygotes fed an atherogenic diet show only minimal destruction of the atherosclerotic aorta wall relative to Apoetm1Bres mice
• in double mutants, the media remain largely intact with continuous elastic membranes and multiple smooth-muscle cell layers; no infiltrating macrophages are detected, except at the base of the intimal plaque
• double mutants show no atherosclerotic aneurysmal dilation or rupture whereas Apoetm1Bres mice exhibit a >50% dilation in the diameter of the abdominal aorta


Mouse Genome Informatics
cx6
    Plautm1Mlg/Plautm1Mlg
Thbdtm2Rdr/Thbdtm2Rdr

involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging


Mouse Genome Informatics
cx7
    Plattm1Mlg/Plattm1Mlg
Plautm1Mlg/Plautm1Mlg

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• double homozygotes exhibit a reduced lifespan with 17% dying at ~17 weeks of age
• 9 out of 22 double homozygotes survive until the end of an observation period of 30-40 weeks; only 3 out of 10 double mutants survive until 40-50 weeks

cellular
• pre-terminal double mutants display intestinal adhesions and occasionally ischemic tissue necrosis (uterus and intestines), possibly due to thrombosis

digestive/alimentary system
• at 8-12 weeks of age, 37% of double homozygotes display rectal prolapse of a non-infectious origin
• in double mutants, rectal prolapse develops with variable penetrance and onset but appears significantly earlier and at a much higher incidence than in single mutant mice

growth/size
• at 8-12 weeks of age, 5% of double homozygotes show extensive non-healing ulcerations at the ears around the ear tag and the face
• at ~17 weeks, 17% of double homozygotes appear runted prior to death
• at 23 weeks, the body weight of double homozygotes is approximately 2/3 that of wild-type mice
• at ~17 weeks, 17% of double homozygotes exhibit cachexia prior to death
• after 3 weeks of age, double homozygotes appear growth retarded relative to wild-type mice

hearing/vestibular/ear
• at 8-12 weeks of age, 5% of double homozygotes show extensive non-healing ulcerations at the ears around the ear tag and the face

reproductive system
• double homozygous breeding pairs produce slightly fewer offspring per litter than wild-type breeding pairs
• double homozygotes display a significant reduction in fertility possibly because of poor health or large fibrin deposition in the gonads

respiratory system
• at ~17 weeks, 17% of double homozygotes exhibit dyspnea prior to death

vision/eye
• at 8-12 weeks of age, 5% of double homozygotes exhibit extensive non-healing ulcerations at the eyelids

homeostasis/metabolism
• double homozygotes exhibit a severe reduction in the rate of spontaneous plasma clot lysis relative to wild-type or Plattm1Mlg mutant mice
• in double mutants, lysis of 125I-fibrin-labeled pulmonary plasma clots remains significantly lower for up to 48 hrs but is not significantly different after 72 hrs
• pre-terminal double mutants exhibit spontaneous fibrin deposits in the liver, intestines, gonads, lungs, in non-healing ulcerations of the skin, ears and prolapsed rectum, and occasionally in the kidneys

craniofacial
• at 8-12 weeks of age, 5% of double homozygotes show extensive non-healing ulcerations at the ears around the ear tag and the face


Mouse Genome Informatics
cx8
    Plautm1Mlg/Plautm1Mlg
Tg(RIP1-Tag)2Dh/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• at 13.5 weeks (end stage), mice homozygous for Plautm1Mlg and hemizygous for Tg(RIP1-Tag)2Dh show no differences in the number of angiogenic islets or collective tumor growth relative to Tg(RIP1-Tag)2Dh hemizygotes

cardiovascular system
N
• at 10.5 weeks of age, mice homozygous for Plautm1Mlg and hemizygous for Tg(RIP1-Tag)2Dh show no differences in the frequency of angiogenic switching among premalignant islets relative to RIP1-Tag2 hemizygotes (J:65019)