Phenotypes Associated with This Genotype

Genotype
MGI:5300824

• Allelic Composition: Tg(Tnfsf13b)1Fma/Tg(Tnfsf13b)1Fma
• Genetic Background: involves: C57BL/6 * DBA/2

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

mortality/aging

premature death ( J:178227 )

immune system

increased B cell number ( J:178227 )

• mutants exhibit an increased percentage of B cells in mucosal lymphoid tissues, including the gut lamina propria and the mesenteric lymph nodes, and in the spleen

• both specific pathogen free and germ-free mutants exhibit B cell hyperplasia in the spleen

increased transitional stage T2 B cell number ( J:178227 )

• both specific pathogen free and germ-free mutants exhibit expanded percentages of transitional 2 B cells

increased marginal zone B cell number ( J:178227 )

• both specific pathogen free and germ-free mutants exhibit expanded percentages of splenic marginal zone B cells

abnormal immunoglobulin level ( J:178227 )

• serum IgA level in germ-free mutants is decreased about 100-fold compared to specific-pathogen free mutants but is similar to those for germ-free wild-type mutants

• germ-free mutants do not exhibit increased IgA in plasma cells in the gut and deposition of IgA in the glomeruli as is seen in conventionally housed specific pathogen free mutants

increased immunoglobulin level ( J:178227 )

• while IgM and IgA levels are elevated in mutants, serum IgG levels and antinuclear IgG antibodies are not elevated in mutants

increased IgA level ( J:178227 )

• by 8 months of age, most mutants exhibit IgA mesangial deposition in the glomeruli, however little C4 deposition is seen

• IgA serum levels are elevated by 8 weeks of age in males and remain at this elevated level until 6 to 8 months of age, at which point, IgA levels begin to drop

• in most females, serum IgA levels do not rise

• serum IgA in mutants is aberrantly glycosylated, with reduced amounts of terminal galactose and sialic acid, is polymeric and is not associated with the secretory component

• germ-free mutants colonized with a limited commensal microbiota called altered Schaedler flora (ASF) at 6 weeks of age exhibit an increase in serum IgA levels that continue to increase until about 3.5 weeks and then stabilize compared to wild-type mice colonized with ASF

• conventionally housed specific pathogen free mutants colonized with ASF exhibit widespread dissemination of IgA+ plasma cells in the periphery while germ-free mutants housed in a barrier facility do not show IgA+ plasma cells in the periphery after colonization, indicating that the hyper-IgA syndrome is influenced by ongoing-commensual-dependent signaling in the intestine

increased IgM level ( J:178227 )

• mutants with mild proteinuria at 6-8 months of age, exhibit mesangial deposits of IgM in the glomeruli

• IgM serum levels are elevated by 8 weeks of age

kidney inflammation ( J:178227 )

• mutants develop severe and fatal nephritis by 17 months of age

• males develop nephritis faster than females and this gender bias is thought to result from sexual dimorphism in expression in the kidneys of the alpha1-antitrypsin driven transgene

homeostasis/metabolism

increased urine protein level ( J:178227 )

albuminuria ( J:178227 )

• by 6 months of age, mutants exhibit modest albuminuria that gets worse with age

hematopoietic system

increased B cell number ( J:178227 )

• mutants exhibit an increased percentage of B cells in mucosal lymphoid tissues, including the gut lamina propria and the mesenteric lymph nodes, and in the spleen

• both specific pathogen free and germ-free mutants exhibit B cell hyperplasia in the spleen

increased transitional stage T2 B cell number ( J:178227 )

• both specific pathogen free and germ-free mutants exhibit expanded percentages of transitional 2 B cells

increased marginal zone B cell number ( J:178227 )

• both specific pathogen free and germ-free mutants exhibit expanded percentages of splenic marginal zone B cells

abnormal immunoglobulin level ( J:178227 )

• serum IgA level in germ-free mutants is decreased about 100-fold compared to specific-pathogen free mutants but is similar to those for germ-free wild-type mutants

• germ-free mutants do not exhibit increased IgA in plasma cells in the gut and deposition of IgA in the glomeruli as is seen in conventionally housed specific pathogen free mutants

increased immunoglobulin level ( J:178227 )

• while IgM and IgA levels are elevated in mutants, serum IgG levels and antinuclear IgG antibodies are not elevated in mutants

increased IgA level ( J:178227 )

• by 8 months of age, most mutants exhibit IgA mesangial deposition in the glomeruli, however little C4 deposition is seen

• IgA serum levels are elevated by 8 weeks of age in males and remain at this elevated level until 6 to 8 months of age, at which point, IgA levels begin to drop

• in most females, serum IgA levels do not rise

• serum IgA in mutants is aberrantly glycosylated, with reduced amounts of terminal galactose and sialic acid, is polymeric and is not associated with the secretory component

• germ-free mutants colonized with a limited commensal microbiota called altered Schaedler flora (ASF) at 6 weeks of age exhibit an increase in serum IgA levels that continue to increase until about 3.5 weeks and then stabilize compared to wild-type mice colonized with ASF

• conventionally housed specific pathogen free mutants colonized with ASF exhibit widespread dissemination of IgA+ plasma cells in the periphery while germ-free mutants housed in a barrier facility do not show IgA+ plasma cells in the periphery after colonization, indicating that the hyper-IgA syndrome is influenced by ongoing-commensual-dependent signaling in the intestine

increased IgM level ( J:178227 )

• mutants with mild proteinuria at 6-8 months of age, exhibit mesangial deposits of IgM in the glomeruli

• IgM serum levels are elevated by 8 weeks of age

renal/urinary system

increased urine protein level ( J:178227 )

albuminuria ( J:178227 )

• by 6 months of age, mutants exhibit modest albuminuria that gets worse with age

abnormal renal glomerulus morphology ( J:178227 )

• kidneys show expanded glomeruli and glomerular capillary thickening but no sclerosis

• with age, mutants display severe, global, and diffuse deposition of hyaline material in the glomeruli

abnormal mesangial cell morphology ( J:178227 )

• kidneys show rare mild mesangial cell proliferation but no glomerular sclerosis, tubular atrophy, or interstitial perivascular infiltration

expanded mesangial matrix ( J:178227 )

• kidneys exhibit segmental multifocal expansion of the mesangial matrix with hyaline materials

renal glomerulus atrophy ( J:178227 )

• mild focal tubular atrophy

abnormal kidney physiology ( J:178227 )

• mutants exhibit impaired kidney function by 14-15 months of age that is preceded by an elevation in IgA at 8-10 months of age

kidney inflammation ( J:178227 )

• mutants develop severe and fatal nephritis by 17 months of age

• males develop nephritis faster than females and this gender bias is thought to result from sexual dimorphism in expression in the kidneys of the alpha1-antitrypsin driven transgene

cellular

abnormal mesangial cell morphology ( J:178227 )

• kidneys show rare mild mesangial cell proliferation but no glomerular sclerosis, tubular atrophy, or interstitial perivascular infiltration

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
IgA glomerulonephritis		DOID:2986	OMIM:161950	J:178227