Phenotypes Associated with This Genotype

Genotype
MGI:3619520

• Allelic Composition: Fbn1^Tsk/Fbn1⁺
• Genetic Background: B6.Cg-Fbn1^Tsk

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

Fbn1^Tsk/Fbn1⁺ skin exhibits abnormal organization and distribution of microfibrillar arrays

respiratory system

lung inflammation ( J:6566 , J:30961 )

• presence of focal collections of mononuclear phagocytes, lymphocytes, and neutrophils in the interstitium (J:6566)

• increased numbers of alveolar macrophages and neutrophils in the interstitium (J:30961)

alveolitis ( J:6566 , J:15018 , J:30961 )

• presence of focal collections of mononuclear phagocytes, lymphocytes, and neutrophils within alveolar air spaces (J:6566)

• macrophage-neutrophil alveolitis is seen at 3 weeks of age, at a time when emphysematous lesions are not yet present (J:15018)

• exhibit alveolitis, with increased numbers of alveolar macrophages and neutrophils in the alveolar lumens (J:30961)

abnormal lung morphology ( J:30961 )

dilated pulmonary alveolar duct ( J:15018 , J:30961 )

• enlarged alveolar ducts are first seen at 3 weeks of age (J:15018)

• dilation of alveolar ducts (J:30961)

abnormal pulmonary alveolus morphology ( J:1326 , J:3934 , J:6566 , J:15018 , J:30961 )

• exhibit formation of bullae and subpleural cysts and fragmented elastin in alveolar walls (J:1326)

• enlargement of air spaces with numerous subpleural cysts and scattered bullae (J:6566)

• at 3 weeks of age, alveoli are flattened but not enlarged, however by 4-6 weeks af age, alveoli are enlarged (J:15018)

• thinning and destruction of alveolar walls (J:30961)

• numerous broken alveolar septa and bullous lesions (J:30961)

• alveoli are irregular in size, with most appearing enlarged (J:30961)

decreased pulmonary alveolus wall thickness ( J:30961 )

• thinning and destruction of alveolar walls

overexpanded pulmonary alveolus ( J:15018 , J:30961 , J:68448 )

• develop enlarged alveoli between 4 and 6 weeks of age (J:15018)

• distension of many alveoli (J:30961)

• enlarged alveoli are 3 to 4 times larger than normal and show a histologic picture of emphysema (J:68448)

abnormal pulmonary interalveolar septum morphology ( J:3934 )

• progressive destruction of alveolar septa and increase in collagen deposition in the septa that may result from repair of the lung destruction

abnormal alveolar pore morphology ( J:6566 , J:30961 )

• increase in the number and size of the pores of Kohn (J:6566)

• alveolar pores in septa are variable in size and increased in number (J:30961)

thick pulmonary interalveolar septum ( J:3934 )

• diffuse thickening of the septa not affected by emphysematous changes, resulting from a progressive increase in collagen

emphysema ( J:3934 , J:6566 , J:15018 )

• emphysematous lesions are seen at 4 weeks of age (J:15018)

abnormal bronchiole morphology ( J:30961 )

• dilation of bronchioles

increased total lung capacity ( J:6566 , J:30961 )

• increase in total lung capacity (J:30961)

increased lung compliance ( J:6566 , J:30961 )

• increase in lung compliance (J:30961)

immune system

abnormal uterine NK cell morphology ( J:1377 )

♀ • distribution of granulated metrial gland cells, a uterine natural killer-like cell subset, is abnormal during pregnancy, with cells seen in the antimesometral and lateral decidual regions at E8.5 and in regions between implantation sites until E10.5, however their differentiation progresses normally

increased mast cell number ( J:8047 )

• increase in number and enhanced degree of degranulation of mast cells in the skin

increased susceptibility to type IV hypersensitivity reaction ( J:7185 )

• develop cell-mediated immunity to elastase-soluble murine lung peptides with age while delayed-type hypersensitivity responses to type I or type IV collagen are not detected

increased autoantibody level ( J:14166 , J:21987 )

• develop autoantibodies specific for scleroderma target antigens, with a bias toward the use of V_HJ558 genes and J_H2 and J_K2 segments (J:14166)

• develop anti-nucleolar antibodies and produce significantly higher titers of autoantibodies specific for scleroderma target antigens (topo I, RNA pol I, and Fc gamma R) (J:21987)

lung inflammation ( J:6566 , J:30961 )

• presence of focal collections of mononuclear phagocytes, lymphocytes, and neutrophils in the interstitium (J:6566)

• increased numbers of alveolar macrophages and neutrophils in the interstitium (J:30961)

alveolitis ( J:6566 , J:15018 , J:30961 )

• presence of focal collections of mononuclear phagocytes, lymphocytes, and neutrophils within alveolar air spaces (J:6566)

• macrophage-neutrophil alveolitis is seen at 3 weeks of age, at a time when emphysematous lesions are not yet present (J:15018)

• exhibit alveolitis, with increased numbers of alveolar macrophages and neutrophils in the alveolar lumens (J:30961)

hematopoietic system

abnormal uterine NK cell morphology ( J:1377 )

♀ • distribution of granulated metrial gland cells, a uterine natural killer-like cell subset, is abnormal during pregnancy, with cells seen in the antimesometral and lateral decidual regions at E8.5 and in regions between implantation sites until E10.5, however their differentiation progresses normally

increased mast cell number ( J:8047 )

• increase in number and enhanced degree of degranulation of mast cells in the skin

cardiovascular system

abnormal aorta tunica adventitia morphology ( J:1326 )

• aorta exhibits hyperplasia of loose connective tissue in the adventitia

• collagen fibers in the aorta are increased and microfibrils surrounding elastin in the adventitia of the aorta are not clearly apparent

abnormal heart morphology ( J:17160 , J:24523 )

• 2.5-fold increase in type VI collagen content in myocardium (J:17160)

• collagen deposition is increased in the heart (J:24523)

• type I collagen is increased in the myocardium, perhaps due to reduced activity of negative regulatory sequence (J:24523)

abnormal heart right ventricle morphology ( J:20724 )

• increase in collagen content in the right ventricle at 3 months of age; however, by 16 months of age, collagen content returns to normal levels but there is a shift in collagen type due to an increase in type I collagen, and by 24 months of age, again see an increase in collagen content

heart right ventricle hypertrophy ( J:20724 )

• starts to develop at around 8 months of age

cardiac fibrosis ( J:1562 , J:24523 )

• thyroid hormone treatment decreases collagen synthesis and stimulates regression of cardiac fibrosis (J:1562)

• exhibit myocardial fibrosis (J:24523)

renal/urinary system

abnormal urinary bladder morphology ( J:3616 )

• 70% increase in collagen content and concentration in the bladder at 5-6 months of age

abnormal urinary bladder physiology ( J:3616 )

• functional bladder capacity appears to be greater

polyuria ( J:3616 )

• urinate larger volumes more frequently during the light cycle

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:29151 )

N • no aberrant bleeding time after tail vein nick

reproductive system

abnormal uterine NK cell morphology ( J:1377 )

♀ • distribution of granulated metrial gland cells, a uterine natural killer-like cell subset, is abnormal during pregnancy, with cells seen in the antimesometral and lateral decidual regions at E8.5 and in regions between implantation sites until E10.5, however their differentiation progresses normally

integument

abnormal hypodermis morphology ( J:8047 )

• increase in width of the subcutaneous fibrous layer with increasing age

abnormal skin morphology ( J:7057 )

• significantly greater skin biopsy weights, however percent of water-fat is similar to wild-type

• hexosamine, uronic acid, and total glycosaminoglycan content is increased in skin

abnormal cutaneous collagen fibril morphology ( J:68448 )

• electron micrographs of skin show a predominance of abnormally small diameter collagen fibers and the skin shows abundant irregular and wavy collagen bundles

abnormal cutaneous microfibril morphology ( J:46405 )

• transmission electron microscopy of the upper dermis shows more prominent microfibrillar clusters, which often appear blurred and lacking a discernible striated pattern, but an absence of well-packed elastic fibrils

• although there is a morphologically normal population of skin microfibrils, approximately 45% of the skin microfibril population has abnromal periodic arrays of beads with indistinct filamentous interbeads and extended periodicity of 112 (+/-11) nm relative to 55 (+/-4) nm in normal microfibrils

• the abnormal skin microfibrils have an altered response to calcium chelation by EDTA, with diminished shortening of the periodicity of microfibrils and less prominant appearance of beading compared with control microfibrils, and the large microfibril aggregates fail to dissociate

thick skin ( J:68448 )

• skin is 228 um thick on average instead of the wildtype 132 um

skin fibrosis ( J:26096 , J:68448 )

• develop skin fibrosis which results originally from collagen I and III overexpression and later collagen VI overexpression (J:26096)

• unlike human scleroderma, fibrosis does not manifest Tgfb1 mRNA in areas of abnormal collagen deposition (J:26096)

abnormal skin physiology ( J:8140 , J:68448 )

• cultured skin fibroblasts synthesize almost 5 times more Type I and Type III procollagen mRNA indicating production of excessive amounts of collagen (J:8140)

• fibroblasts synthesize increased collagen both constitutively and in response to IL4 or TGFB, although IL13 does not increase fibroblast collagen synthesis (J:68448)

embryo

abnormal uterine NK cell morphology ( J:1377 )

♀ • distribution of granulated metrial gland cells, a uterine natural killer-like cell subset, is abnormal during pregnancy, with cells seen in the antimesometral and lateral decidual regions at E8.5 and in regions between implantation sites until E10.5, however their differentiation progresses normally

endocrine/exocrine glands

abnormal uterine NK cell morphology ( J:1377 )

♀ • distribution of granulated metrial gland cells, a uterine natural killer-like cell subset, is abnormal during pregnancy, with cells seen in the antimesometral and lateral decidual regions at E8.5 and in regions between implantation sites until E10.5, however their differentiation progresses normally

growth/size/body

heart right ventricle hypertrophy ( J:20724 )

• starts to develop at around 8 months of age

muscle

heart right ventricle hypertrophy ( J:20724 )

• starts to develop at around 8 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Marfan syndrome		DOID:14323	OMIM:154700	J:30961
pulmonary emphysema		DOID:9675	OMIM:130700	J:1326 , J:6566 , J:15018 , J:30961 , J:68448
systemic scleroderma		DOID:418	OMIM:181750	J:7057 , J:7185 , J:8047 , J:21987