Novel gene disruptions, compositions and methods relating thereto

Abstract

The present invention relates to transgenic animals, as well as compositions and methods relating to the characterization of gene function. Specifically, the present invention provides transgenic mice comprising disruptions in PRO194, PRO220, PRO241, PRO284, PRO331, PRO354, PRO355, PRO533, PRO541, PRO725, PRO937, PRO1014, PRO1120, PRO1182, PRO1325, PRO1382, PRO1410, PRO1555, PRO1556, PRO1760, PRO1787, PRO1868, PRO4326, PRO4332, PRO4346, PRO4400, PRO6003, PRO6094, PRO6244, PRO9820, PRO9828, PRO10274, PRO16090, PRO19644, PRO21340, PRO92165, PRO85143, PRO1124, PRO1026 or PRO23370 genes. Such in vivo studies and characterizations may provide valuable identification and discovery of therapeutics and/or treatments useful in the prevention, amelioration or correction of diseases or dysfunctions associated with gene disruptions such as neurological disorders; cardiovascular, endothelial or angiogenic disorders; eye abnormalities; immunological disorders; oncological disorders; bone metabolic abnormalities or disorders; lipid metabolic disorders; or developmental abnormalities.

1 - 149 . (canceled) 
     
     
         150 . A method of identifying an agent that modulates a phenotype associated with a disruption of a gene which encodes for a PRO6003 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of a gene which is an ortholog of a human gene that encodes for the PRO6003 polypeptide;   (b) measuring a physiological characteristic of the non-human transgenic animal of (a);   (c) comparing the measured physiological characteristic of (b) with that of a gender matched wild-type animal, wherein the physiological characteristic of the non-human transgenic animal that differs from the physiological characteristic of the wild-type animal is identified as a phenotype resulting from the gene disruption in the non-human transgenic animal;   (d) administering a test agent to the non-human transgenic animal of (a); and   (e) determining whether the test agent modulates the identified phenotype associated with gene disruption in the non-human transgenic animal.   
     
     
         151 . The method of  claim 150 , wherein the phenotype associated with the gene disruption comprises a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality. 
     
     
         152 . The method of  claim 151 , wherein the neurological disorder is an increased anxiety-like response during open field activity testing. 
     
     
         153 . The method of  claim 151 , wherein the neurological disorder is a decreased anxiety-like response during open field activity testing. 
     
     
         154 . The method of  claim 151 , wherein the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. 
     
     
         155 . The method of  claim 151 , wherein the neurological disorder is an enhanced motor coordination during inverted screen testing. 
     
     
         156 . The method of  claim 151 , wherein the neurological disorder is an impaired motor coordination during inverted screen testing. 
     
     
         157 . The method of  claim 151 , wherein the neurological disorder is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders. 
     
     
         158 . The method of  claim 151 , wherein the eye abnormality is a retinal abnormality. 
     
     
         159 . The method of  claim 151 , wherein the eye abnormality is consistent with vision problems or blindness. 
     
     
         160 . The method of  claim 158 , wherein the retinal abnormality is consistent with retinitis pigmentosa. 
     
     
         161 . The method of  claim 158 , wherein the retinal abnormality is characterized by retinal degeneration or retinal dysplasia. 
     
     
         162 . The method of  claim 158 , wherein the retinal abnormality is consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis. 
     
     
         163 . The method of  claim 151 , wherein the eye abnormality is a cataract. 
     
     
         164 . The method of  claim 163 , wherein the cataract is consistent with systemic diseases such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome. 
     
     
         165 . The method of  claim 151 , wherein the developmental abnormality comprises embryonic lethality or reduced viability. 
     
     
         166 . The method of  claim 151 , wherein the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis. 
     
     
         167 . The method of  claim 151 , wherein the immunological disorders are systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation-associated diseases including graft rejection and graft-versus-host disease. 
     
     
         168 . The method of  claim 151 , wherein said bone metabolic abnormality or disorder is arthritis, osteoporosis or osteopetrosis. 
     
     
         169 . The method of  claim 150 , wherein the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety-like response during open field activity testing; hyperactivity during open field testing; hypoactivity during open field testing; increased exploratory activity during open-field testing; decreased exploratory activity during open-field testing; abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; increased habituation response to a novel environment; increased resistance to stress induced hyperthermia; impaired motor coordination during inverted screen testing; increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; decreased startle response during prepulse inhibition testing; enhanced sensorimotor gating/attention during prepulse inhibition testing; reduced latency to respond in hot plate testing; opthamological abnormalities; retinal depigmentation; cataracts; decreased heart rate; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; increased mean serum triglyceride levels; decreased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; increased uric acid levels; decreased uric acid levels; decreased serum phosphate levels; increased serum phosphate levels; increased bilirubin levels; increased nitrituria; decreased mean serum albumin; liver disorders; decreased mean percentage of natural killer cells; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8+ cells; decreased basophils; decreased lymphocytes; increased mean absolute monocyte count; macrocytic anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit; increased mean platelet count; decreased mean serum IgG1 response to an ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum IgG2a response to an ovalbumin challenge; increased mean serum IgG2a response to an ovalbumin challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; increased hemosiderin pigment in both spleen and bone marrow; increased mean percent of total body fat and total fat mass; increased mean body weight; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased BMC/LBM ratio; increased bone mineral density (BMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM);
 decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased BMC/LBM ratio; decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; osteodystrophy and metastatic calcification; decreased intra-abdominal fat; growth retardation; development abnormalities; multi focal acute and granulomatous inflammation; male infertility; female infertility; testicular degeneration; male hypogonadism; defective or arrested spermatogenesis; decreased testicular weight; inflammatory and degenerative myopathy; alterations in pancreatic acinar cells; enlarged kidneys; kidney disorders; muscle disorders; stunted growth with general reduction in all organ size; growth retardation with reduced viability; and embryonic lethality.   
     
     
         170 . A method of identifying an agent which modulates a behavior associated with a disruption of a gene which encodes for a PRO6003 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of a gene which is an ortholog of a human gene that encodes for a PRO6003 polypeptide;   (b) observing the behavior exhibited by the non-human transgenic animal of (a);   (c) comparing the observed behavior of (b) with that of a gender matched wild-type animal, wherein the observed behavior exhibited by the non-human transgenic animal that differs from the observed behavior exhibited by the wild-type animal is identified as a behavior associated with gene disruption;   (d) administering a test agent to the non-human transgenic animal of (a); and   (e) determining whether the agent modulates the behavior associated with gene disruption.   
     
     
         171 . The method of  claim 170 , wherein the behavior is an increased anxiety-like response during open field activity testing. 
     
     
         172 . The method of  claim 170 , wherein the behavior is a decreased anxiety-like response during open field activity testing. 
     
     
         173 . The method of  claim 170 , wherein the behavior is an abnormal circadian rhythm during home-cage activity testing. 
     
     
         174 . The method of  claim 170 , wherein the behavior is an enhanced motor coordination during inverted screen testing. 
     
     
         175 . The method of  claim 170 , wherein the behavior is an impaired motor coordination during inverted screen testing. 
     
     
         176 . The method of  claim 170 , wherein the behavior is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders. 
     
     
         177 . A method of identifying an agent that ameliorates or modulates a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality associated with a disruption in a gene which encodes for a PRO6003 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of a gene which is an ortholog of a human gene that encodes for a PRO6003 polypeptide;   (b) administering a test agent to said non-human transgenic animal; and   (c) determining whether said test agent ameliorates or modulates the neurological disorder; cardiovascular, endothelial or angiogenic disorder; eye abnormality; immunological disorder; oncological disorder; bone metabolic abnormality or disorder; lipid metabolic disorder; or developmental abnormality in the non-human transgenic animal.   
     
     
         178 . The method of  claim 177 , wherein the neurological disorder is an increased anxiety-like response during open field activity testing. 
     
     
         179 . The method of  claim 177 , wherein the neurological disorder is a decreased anxiety-like response during open field activity testing. 
     
     
         180 . The method of  claim 177 , wherein the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. 
     
     
         181 . The method of  claim 177 , wherein the neurological disorder is an enhanced motor coordination during inverted screen testing. 
     
     
         182 . The method of  claim 177 , wherein the neurological disorder is an impaired motor coordination during inverted screen testing. 
     
     
         183 . The method of  claim 177 , wherein the neurological disorder is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders. 
     
     
         184 . The method of  claim 177 , wherein the eye abnormality is a retinal abnormality. 
     
     
         185 . The method of  claim 177 , wherein the eye abnormality is consistent with vision problems or blindness. 
     
     
         186 . The method of  claim 184 , wherein the retinal abnormality is consistent with retinitis pigmentosa. 
     
     
         187 . The method of  claim 184 , wherein the retinal abnormality is characterized by retinal degeneration or retinal dysplasia. 
     
     
         188 . The method of  claim 184 , wherein the retinal abnormality is consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis. 
     
     
         189 . The method of  claim 177 , wherein the eye abnormality is a cataract. 
     
     
         190 . The method of  claim 189 , wherein the cataract is a systemic disease such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome. 
     
     
         191 . The method of  claim 177 , wherein the developmental abnormality comprises embryonic lethality or reduced viability. 
     
     
         192 . The method of  claim 177 , wherein the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis. 
     
     
         193 . The method of  claim 177 , wherein the immunological disorders are systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease. 
     
     
         194 . The method of  claim 177 , wherein said bone metabolic abnormality or disorder is arthritis, osteoporosis or osteopetrosis. 
     
     
         195 . The method of  claim 177 , wherein the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety-like response during open field activity testing; hyperactivity during open field testing; hypoactivity during open field testing; increased exploratory activity during open-field testing; decreased exploratory activity during open-field testing; abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; increased habituation response to a novel environment; increased resistance to stress induced hyperthermia; impaired motor coordination during inverted screen testing; increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; decreased startle response during prepulse inhibition testing; enhanced sensorimotor gating/attention during prepulse inhibition testing; reduced latency to respond in hot plate testing; opthamological abnormalities; retinal depigmentation; cataracts; decreased heart rate; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; increased mean serum triglyceride levels; decreased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; increased uric acid levels; decreased uric acid levels; decreased serum phosphate levels; increased serum phosphate levels; increased bilirubin levels; increased nitrituria; decreased mean serum albumin; liver disorders; decreased mean percentage of natural killer cells; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8+ cells; decreased basophils; decreased lymphocytes; increased mean absolute monocyte count; macrocytic anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit; increased mean platelet count; decreased mean serum IgG1 response to an ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum IgG2a response to an ovalbumin challenge; increased mean serum IgG2a response to an ovalbumin challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; increased hemosiderin pigment in both spleen and bone marrow; increased mean percent of total body fat and total fat mass; increased mean body weight; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased BMC/LBM ratio; increased bone mineral density (BMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased BMC/LBM ratio; decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; osteodystrophy and metastatic calcification; decreased intra-abdominal fat; growth retardation; development abnormalities; multi focal acute and granulomatous inflammation; male infertility; female infertility; testicular degeneration; male hypogonadism; defective or arrested spermatogenesis; decreased testicular weight; inflammatory and degenerative myopathy; alterations in pancreatic acinar cells; enlarged kidneys; kidney disorders; muscle disorders; stunted growth with general reduction in all organ size; growth retardation with reduced viability; and embryonic lethality.