Mouse Genome Informatics
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    Arntltm1Bra/Arntltm1Bra
B6.129-Arntltm1Bra
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       

Joint abnormalities with ectopic ossification in Arntltm1Bra/Arntltm1Bra mice

mortality/aging
• require euthanasia between 26 - 45 weeks of age due to dehydration and failure to thrive (J:97108)
• most die between 26 and 52 weeks of age (J:110697)
• average lifespan is 37 +/- 12 weeks (J:110697)
• maximum lifespan is 72 weeks of age (J:110697)
• 29% of animals do not survive for 10 months (J:116189)
• display age related sarcopenia and osteoporosis at 40 weeks of age (J:110697)
• mice display a number of age related phenotypes at an earlier age compared to wild-type controls (J:110697)
• mice exhibit age-induced circulatory changes showing accelerated thrombogenicity at an earlier age than wild-type mice (J:191844)

behavior/neurological
• diurnal variation in activity is abolished
• however, ultradian rhythms are maintained and are stronger than any residual circadian rhythms
• diurnal variation in heart rate is abolished
• diurnal variation in mean arterial pressure is abolished
• however, ultradian rhythms are maintained and are stronger than any residual circadian rhythms
• the diurnal variation in restraint induced changes in blood pressure is abolished and the stress induced alteration in blood pressure is lower at ZT12
• seen in mice over 20 weeks of age
• hindquarters appear more affected than forequarters
• seen in mice over 20 weeks of age
• seen in mice over 20 weeks of age
• stiff tail after 20 weeks of age

growth/size
• at 40 weeks of age
• by 52 weeks of age mice are about half the size of wild-type controls
• by 26 weeks of age mice weigh 23% less than controls (J:97108)
• low body weigh relative to wild-type (J:116189)
• progressive weight loss starting after 20 weeks of age (J:97108)
• growth is similar to controls until about 15 weeks of age (J:97108)
• by 20 weeks of age mice are losing about 0.4g/week (J:97108)
• starting between 16 to 26 weeks of age (J:110697)
• starting around 16 - 18 weeks of age

skeleton
N
• despite extensive ectopic calcification, bone mineral density is not significantly different from heterozygous controls (J:97108)
• by 11 weeks of age calcification of the calcaneal tendon is seen (J:97108)
• by 26 weeks of age extensive calcification of the calcaneal tendon is seen (J:97108)
• by 36 weeks of age chondrification and calcification is seen in the lateral collateral ligament and cruciate ligaments (J:97108)
• calcification/ossification appears to be limited to tendons closely associated with bone insertion sites in the appendicular and axial skeleton (J:97108)
• significant calcaneal tendon calcification (J:116189)
• progressive calcification is seen in areas around bone cartilage junctions in the rib cage with calcified nodules seen at costal chondral and costal sternal junctions
• costal sternal junctions show proliferative bony bridging from the costal cartilage to the sternum
• however, muscle fiber attachment appears normal
• costal sternal junctions show proliferative bony bridging from the costal cartilage to the sternum
• costal cartilage shows increased matrix deposition and bone proliferation
• by 40 weeks of age calcification around bone cartilage junctions results in a severe distortion of the anatomy of the ribs
• at 35 weeks of age evidence of spinal compression is seen
• at 26 weeks of age calcification is seen in the sacral and thoracic regions but not in the lumbar region
• at 40 weeks of age
• in the knee by 26 weeks of age increased proliferation is seen in the synovial fibroblasts
• at 6 and 8 weeks of age small areas of calcification extending from the insertion of the calcaneal tendon are seen in the tarsocrural joint
• by 11 weeks of age, calcified nodules are often seen on the lateral side of the tarsal joint
• by 26 weeks of age, calcified bridging is seen between tarsal bones
• progressive calcification is seen in areas around bone cartilage junctions in the rib cage with calcified nodules seen at costal chondral and costal sternal junctions
• prominent calcified areas extend from the patella as well as along the medial collateral ligament
• by 26 weeks of age, calcified bridging is seen between tarsal bones
• by 35 weeks of age, severe bony ankylosis is seen obscuring the normal anatomy of the tarsocrural joint
• at 35 weeks of age bridging ankylosis is seen on both the dorsal and ventral aspects of the intervertebral joints throughout the thoracic spine
• large osteophytes bridge the sacral vertebrae and complete fusion is seen between S2 and S3 at 35 weeks of age
• by 26 weeks of age calcification of the medial collateral ligament is seen
• by 36 weeks of age chondrification and calcification is seen in the lateral collateral ligament and cruciate ligaments
• calcification/ossification appears to be limited to ligaments closely associated with bone insertion sites in the appendicular and axial skeleton
• by 40 weeks of age ectopic ossification is seen in nearly every joint
• at 26 weeks of age moderate osteophyte formation is seen at the junction of vertebral bodies in the sacral and thoracic regions
• at 35 weeks of age osteophyte formation is seen at the junction of vertebral bodies in the lumbar region

homeostasis/metabolism
• levels of osteocalcin are increased
• the diurnal variation in restraint induced changes in adrenaline level is abolished
• at both Zeitgeber time (ZT) 2 and ZT14
• increase in the percentage of plasma factor VII at 30 weeks of age (J:191844)
• increase in the percentage of plasma factor VIII at 10, but not 30, weeks of age (J:191844)
• increase in the level of plasma fibrinogen at 10 and 30 weeks of age (J:191844)
• prolongation of the activated partial thrombosplastin time and a shortening of the prothrombin time by 1.6 seconds in 10 week old mice and 0.8 seconds in 30 week old mice, as well as increased plasma fibrinogen, factor VII and VIII levels indicate a hypercoagulable state that increases with age (J:191844)
• in vascular injury-induced thrombosis, 10 week old mutants show shortened arteriolar and venular occlusion times, indicating early thrombogenicity (J:191844)
• numerous thrombi are seen in the venous sinus of penile sections from older males with priapism; thrombi contain platelets and fibrin and fibrin-rich laminar thrombus formation is seen extensively lining the endothelium (J:191844)
• in vascular injury-induced thrombosis, 10 week old mutants show shortened arteriolar and venular occlusion times, indicating early thrombogenicity (J:191844)
• after 20 weeks of age appear progressively dehydrated
• basal nitric oxide release is attenuated in the thoracic aorta at 30 weeks of age (J:191844)
• at ZT10 in 40 week old mice, the accumulation of reactive oxygen species is increased in the kidney, heart and spleen but decreased in the liver relative to time and age matched controls
• increase in reactive oxygen species accumulation is age and tissue dependent

reproductive system
• detectable by 10 weeks of age and becoming more pronounced with age (J:110697)
• at 40 weeks of age (J:110697)
• mutants develop spontaneous priapism that increases with age, from 0% at 10 weeks to 8% at 20-25 weeks, and 60% at 25-30 weeks, which is not seen in wild-type mice at any age (J:191844)
• numerous thrombi are seen in the venous sinus of penile sections; thrombi contain platelets and fibrin and fibrin-rich laminar thrombus formation is seen extensively lining the endothelium (J:191844)

adipose tissue
• at 40 weeks of age but not at 10 weeks of age
• at 40 weeks of age

hematopoietic system
N
• at 10 and 40 weeks of age no differences are detected in the numbers of red blood cells or platelets (J:110697)
• despite an increase in leukocytes, lower numbers of rolling leukocytes over endothelium when activated with A23187 are seen in mutants compared to wild-type at both 10 and 30 weeks of age (J:191844)
• decrease in the number of white blood cells at 40 weeks of age compared to age matched controls
• the total number and percentage of lymphocytes are decreased at 40 weeks of age
• decrease in basophils at 30 weeks of age (J:191844)
• increase in white blood cell count at 10, but not 30, weeks of age (J:191844)
• increase in eosinophils at 10, but not 30, weeks of age (J:191844)
• increase in lymphocytes at 10, but not 30, weeks of age (J:191844)
• the total number and percentage of monocytes are increased at 40 weeks of age
• the total number and percentage of neutrophils are increased at 40 weeks of age (J:110697)
• neutrophil numbers are increased 2-fold at 10 weeks of age and 1.2-fold at 30 weeks of age (J:191844)
• increase in platelet count at 30 weeks of age (J:191844)
• despite high platelet numbers at 30 weeks of age, platelet aggregation assays show a normal platelet response to the agonist ADP (J:191844)
• density of von Willebrand Factor-positive megakaryocytes in 30 week old bone marrow is higher than in controls (J:191844)
• at 30 and 40 weeks of age

cardiovascular system
• diurnal variation in heart rate is abolished
• diurnal variation in mean arterial pressure is abolished
• however, ultradian rhythms are maintained and are stronger than any residual circadian rhythms
• the diurnal variation in restraint induced changes in blood pressure is abolished and the stress induced alteration in blood pressure is lower at ZT12
• corneal inflammation begins as massive neovascularization
• smooth muscle cell density is higher in aorta segments at 10, but not 30, weeks of age (J:191844)
• at 40 weeks of age
• endothelium-dependent vasomotor responses are altered, with an increase of phenylephrine contraction induced by NOS inhibitors and suppression of acetylcholine-muscarinic receptor-induced endothelium-dependent relaxations in aortic rings of mutants, particularly at 30 weeks of age (J:191844)
• however, mutants exhibit normal contractility of aortic smooth muscle cells as indicated by normal contractile responses to the alpha1-adrenoreceptor agonist phenylephrine when eNOS activity is blocked and normal responsiveness to exogenous nitric oxide released by the nitric oxide donor diethylamine NONOate (J:191844)
• smooth muscle cells show an increase of phenylephrine evoked contraction induced by NOS inhibitors in aortic rings of mutants, particularly at 30 weeks of age (J:191844)
• smooth muscle cells exhibit suppression of acetylcholine-muscarinic receptor-induced endothelium-dependent relaxations in aortic rings of mutants, particularly at 30 weeks of age (J:191844)
• only during the active phase
• expected elevation during the dark phase is absent
• decreased in both the light and dark phases compared to wild-type controls

vision/eye
• corneal inflammation begins as ulceration of the outer layer of the cornea
• keratin deposits are seen
• corneal inflammation begins as massive neovascularization
• at 40 weeks of age over 50% of mice display progressive corneal inflammation
• corneal inflammation begins as massive neovascularization, lymphoid cell infiltration and ulceration of the outer layer of the cornea
• ulceration disrupts the stromal structure
• the lens posterior zone contains enlarged infiltrating epithelial cells
• the density of cortical and nucleus fibers is increased
• by 30 weeks of age all mice have various grades of cataracts in one or both eyes

muscle
• smooth muscle cell density is higher in aorta segments at 10, but not 30, weeks of age (J:191844)
• endothelium-dependent vasomotor responses are altered, with an increase of phenylephrine contraction induced by NOS inhibitors and suppression of acetylcholine-muscarinic receptor-induced endothelium-dependent relaxations in aortic rings of mutants, particularly at 30 weeks of age (J:191844)
• however, mutants exhibit normal contractility of aortic smooth muscle cells as indicated by normal contractile responses to the alpha1-adrenoreceptor agonist phenylephrine when eNOS activity is blocked and normal responsiveness to exogenous nitric oxide released by the nitric oxide donor diethylamine NONOate (J:191844)
• smooth muscle cells show an increase of phenylephrine evoked contraction induced by NOS inhibitors in aortic rings of mutants, particularly at 30 weeks of age (J:191844)
• smooth muscle cells exhibit suppression of acetylcholine-muscarinic receptor-induced endothelium-dependent relaxations in aortic rings of mutants, particularly at 30 weeks of age (J:191844)
• at 40 weeks of age
• by 11 weeks of age calcification of the calcaneal tendon is seen (J:97108)
• by 26 weeks of age extensive calcification of the calcaneal tendon is seen (J:97108)
• by 36 weeks of age chondrification and calcification is seen in the lateral collateral ligament and cruciate ligaments (J:97108)
• calcification/ossification appears to be limited to tendons closely associated with bone insertion sites in the appendicular and axial skeleton (J:97108)
• significant calcaneal tendon calcification (J:116189)

renal/urinary system
• at 40 weeks of age

respiratory system
• at 40 weeks of age

immune system
• despite an increase in leukocytes, lower numbers of rolling leukocytes over endothelium when activated with A23187 are seen in mutants compared to wild-type at both 10 and 30 weeks of age (J:191844)
• decrease in the number of white blood cells at 40 weeks of age compared to age matched controls
• the total number and percentage of lymphocytes are decreased at 40 weeks of age
• decrease in basophils at 30 weeks of age (J:191844)
• increase in white blood cell count at 10, but not 30, weeks of age (J:191844)
• increase in eosinophils at 10, but not 30, weeks of age (J:191844)
• increase in lymphocytes at 10, but not 30, weeks of age (J:191844)
• the total number and percentage of monocytes are increased at 40 weeks of age
• the total number and percentage of neutrophils are increased at 40 weeks of age (J:110697)
• neutrophil numbers are increased 2-fold at 10 weeks of age and 1.2-fold at 30 weeks of age (J:191844)
• at 30 and 40 weeks of age
• increase in the level of plasma fibrinogen at 10 and 30 weeks of age (J:191844)
• at 40 weeks of age over 50% of mice display progressive corneal inflammation
• corneal inflammation begins as massive neovascularization, lymphoid cell infiltration and ulceration of the outer layer of the cornea

endocrine/exocrine glands
• detectable by 10 weeks of age and becoming more pronounced with age (J:110697)
• at 40 weeks of age (J:110697)

integument
• at 40 weeks of age but not at 10 weeks of age
• at 30 weeks of age hair regrowth after shaving is delayed with only 1 of 5 mice showing partial regrowth after 3 months
• however, at 10 weeks of age hair regrowth is normal

cellular
• despite an increase in leukocytes, lower numbers of rolling leukocytes over endothelium when activated with A23187 are seen in mutants compared to wild-type at both 10 and 30 weeks of age (J:191844)

Mouse Models of Human Disease
OMIM IDRef(s)
Priapism, Familial Idiopathic 176620 J:191844