Phenotypes associated with this allele

• Allele Symbol: Inpp5d^tm1Rkh
• Allele Name: targeted mutation 1, R Keith Humphries
• Allele ID: MGI:2386884
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Inpp5d^tm1Rkh/Inpp5d^tm1Rkh	involves: 129S1/Sv * 129X1/SvJ	MGI:5319308
hm2	Inpp5d^tm1Rkh/Inpp5d^tm1Rkh	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3838992
hm3	Inpp5d^tm1Rkh/Inpp5d^tm1Rkh	involves: 129S1/Sv * 129X1/SvJ * C57BL/6J	MGI:3716805
cx4	Il6^tm1Kopf/Il6^tm1Kopf Inpp5d^tm1Rkh/Inpp5d^tm1Rkh	involves: 129 * C57BL/6	MGI:3838993
cx5	Inpp5d^tm1Rkh/Inpp5d^tm1Rkh Rag1^tm1(GFP)Imku/Rag1^+	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA	MGI:3838991

Genotype
MGI:5319308

hm1

• Allelic Composition: Inpp5d^tm1Rkh/Inpp5d^tm1Rkh
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

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

skeleton

abnormal skeleton morphology ( J:78771 )

abnormal long bone morphology ( J:78771 )

• cross sectional area and moment of inertia reduced for femurs

short femur ( J:78771 )

• slightly but significantly shorter than in controls

abnormal long bone metaphysis morphology ( J:78771 )

• extends only half as far into marrow cavity as in controls

abnormal bone structure ( J:78771 )

abnormal osteoclast morphology ( J:78771 )

• 2.6 fold increase in size with a large number of nuclei

• similar to condition in human Paget disease

abnormal osteoclast differentiation ( J:78771 )

• macrophage show increased sensitivity to M-CSF and RANKL

increased osteoclast cell number ( J:78771 )

• two fold increase in osteoclast number in tibias at around 41 days of age

decreased bone mineral density ( J:78771 )

• reduced in long bones

decreased compact bone thickness ( J:78771 )

abnormal trabecular bone morphology ( J:78771 )

• trabecular separation reduced

decreased trabecular bone volume ( J:78771 )

• reduced by 1/3

decreased bone trabecula number ( J:78771 )

decreased trabecular bone thickness ( J:78771 )

abnormal skeleton physiology ( J:78771 )

abnormal osteoclast physiology ( J:78771 )

• hyperresorptive

• when cultured on whale dentin, more surface dentin is resorbed

• deeper resorptive pits generated than for controls

• osteoblast activity is normal

decreased bone strength ( J:78771 )

• diaphyseal bone strength is reduced (rigidity, ultimate moment, fracture energy)

cellular

decreased apoptosis ( J:78771 )

• reduced apoptosis of osteoclasts in culture

abnormal osteoclast differentiation ( J:78771 )

• macrophage show increased sensitivity to M-CSF and RANKL

abnormal macrophage chemotaxis ( J:110864 )

• greater chemotaxic response of bone marrow macrophage to stromal cell-derived factor 1

increased mast cell degranulation ( J:120426 )

• bone marrow mast cells primed with anti-dinitrophenyl IgE and cross-linked with DNP-human serum albumin lose 80% of granule content

• intracellular Calcium increases more than in controls

immune system

abnormal osteoclast morphology ( J:78771 )

• 2.6 fold increase in size with a large number of nuclei

• similar to condition in human Paget disease

abnormal osteoclast differentiation ( J:78771 )

• macrophage show increased sensitivity to M-CSF and RANKL

increased osteoclast cell number ( J:78771 )

• two fold increase in osteoclast number in tibias at around 41 days of age

increased circulating interleukin-6 level ( J:78771 )

• serum levels markedly increased over levels in controls

abnormal cell-mediated immunity ( J:110864 )

abnormal macrophage chemotaxis ( J:110864 )

• greater chemotaxic response of bone marrow macrophage to stromal cell-derived factor 1

increased mast cell degranulation ( J:120426 )

• bone marrow mast cells primed with anti-dinitrophenyl IgE and cross-linked with DNP-human serum albumin lose 80% of granule content

• intracellular Calcium increases more than in controls

abnormal B cell physiology ( J:110864 )

• greater chemotaxic response of bone marrow B cells to stromal cell-derived factor 1

• increased migration of spleen cells

• enhanced migration response to B-lymphocyte chemoattractant

abnormal T cell physiology ( J:110864 )

• greater chemotaxic response of double negative and double positive cells to stromal cell-derived factor 1

abnormal CD4-positive, alpha-beta T cell physiology ( J:110864 )

• greater chemotaxic response of progenitor CD4+ cells of the thymus to stromal cell-derived factor 1

• increased migration of spleen cells

abnormal CD8-positive, alpha-beta T cell physiology ( J:110864 )

• greater chemotaxic response of progenitor CD8+ cells of the thymus to stromal cell-derived factor 1

abnormal osteoclast physiology ( J:78771 )

• hyperresorptive

• when cultured on whale dentin, more surface dentin is resorbed

• deeper resorptive pits generated than for controls

• osteoblast activity is normal

respiratory system

pulmonary edema ( J:100868 )

• increased interstitial lung edema relative to controls after acute lung injury induced by intratracheal peptidoglycan administration

• increased neutrophil infiltration

hematopoietic system

abnormal macrophage chemotaxis ( J:110864 )

• greater chemotaxic response of bone marrow macrophage to stromal cell-derived factor 1

increased mast cell degranulation ( J:120426 )

• bone marrow mast cells primed with anti-dinitrophenyl IgE and cross-linked with DNP-human serum albumin lose 80% of granule content

• intracellular Calcium increases more than in controls

abnormal osteoclast morphology ( J:78771 )

• 2.6 fold increase in size with a large number of nuclei

• similar to condition in human Paget disease

abnormal osteoclast differentiation ( J:78771 )

• macrophage show increased sensitivity to M-CSF and RANKL

increased osteoclast cell number ( J:78771 )

• two fold increase in osteoclast number in tibias at around 41 days of age

abnormal B cell physiology ( J:110864 )

• greater chemotaxic response of bone marrow B cells to stromal cell-derived factor 1

• increased migration of spleen cells

• enhanced migration response to B-lymphocyte chemoattractant

abnormal T cell physiology ( J:110864 )

• greater chemotaxic response of double negative and double positive cells to stromal cell-derived factor 1

abnormal CD4-positive, alpha-beta T cell physiology ( J:110864 )

• greater chemotaxic response of progenitor CD4+ cells of the thymus to stromal cell-derived factor 1

• increased migration of spleen cells

abnormal CD8-positive, alpha-beta T cell physiology ( J:110864 )

• greater chemotaxic response of progenitor CD8+ cells of the thymus to stromal cell-derived factor 1

abnormal osteoclast physiology ( J:78771 )

• hyperresorptive

• when cultured on whale dentin, more surface dentin is resorbed

• deeper resorptive pits generated than for controls

• osteoblast activity is normal

abnormal bone marrow cell physiology ( J:110864 )

• chemokine suppression of myeloid progenitor cells is eliminated

limbs/digits/tail

short femur ( J:78771 )

• slightly but significantly shorter than in controls

homeostasis/metabolism

increased circulating interleukin-6 level ( J:78771 )

• serum levels markedly increased over levels in controls

pulmonary edema ( J:100868 )

• increased interstitial lung edema relative to controls after acute lung injury induced by intratracheal peptidoglycan administration

• increased neutrophil infiltration

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Paget's disease of bone		DOID:5408	OMIM:PS167250	J:78771

Genotype
MGI:3838992

hm2

• Allelic Composition: Inpp5d^tm1Rkh/Inpp5d^tm1Rkh
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

immune system

intestinal inflammation ( J:173301 )

• immune cell infiltrates form granuloma-like structures with multinucleate giant cells

• granulocyte/monocyte, macrophage, and T cells found

ileum inflammation ( J:173301 )

• spontaneous inflammation mostly restricted to the distal 1/3 of the ileum

• onset between 4 and 8 weeks of age

decreased pro-B cell number ( J:117320 )

• the percentage of CD19⁺ B cell progenitors in the bone marrow is decreased by almost 20-fold

abnormal myelopoiesis ( J:117320 )

• 78% of mutant bone marrow cells are Mac-1⁺ compared to 56% in wild-type

abnormal interleukin level ( J:173301 )

• increased levels of IL-4, IL-13, and IL-23

increased circulating interleukin-6 level ( J:117320 )

• mice have no detectable IL-6 levels at birth but levels reach 2 ng/ml by 4 weeks of age

hematopoietic system

decreased pro-B cell number ( J:117320 )

• the percentage of CD19⁺ B cell progenitors in the bone marrow is decreased by almost 20-fold

abnormal myelopoiesis ( J:117320 )

• 78% of mutant bone marrow cells are Mac-1⁺ compared to 56% in wild-type

digestive/alimentary system

abnormal intestine morphology ( J:173301 )

abnormal intestinal goblet cell morphology ( J:173301 )

• hypertrophy

abnormal intestinal smooth muscle morphology ( J:173301 )

• thickened muscularis externa by 8 weeks of age, particularly the circular muscle layer

abnormal ileum morphology ( J:173301 )

• collagen increased 2.1 fold

• increased fibroblasts

intestinal inflammation ( J:173301 )

• immune cell infiltrates form granuloma-like structures with multinucleate giant cells

• granulocyte/monocyte, macrophage, and T cells found

ileum inflammation ( J:173301 )

• spontaneous inflammation mostly restricted to the distal 1/3 of the ileum

• onset between 4 and 8 weeks of age

homeostasis/metabolism

abnormal interleukin level ( J:173301 )

• increased levels of IL-4, IL-13, and IL-23

increased circulating interleukin-6 level ( J:117320 )

• mice have no detectable IL-6 levels at birth but levels reach 2 ng/ml by 4 weeks of age

muscle

abnormal intestinal smooth muscle morphology ( J:173301 )

• thickened muscularis externa by 8 weeks of age, particularly the circular muscle layer

cellular

abnormal intestinal goblet cell morphology ( J:173301 )

• hypertrophy

Genotype
MGI:3716805

hm3

• Allelic Composition: Inpp5d^tm1Rkh/Inpp5d^tm1Rkh
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

mortality/aging

premature death ( J:48193 )

• some mice become moribund at 4 weeks and 50% of mice die by 10 weeks

hematopoietic system

abnormal macrophage chemotaxis ( J:48193 )

• the air spaces are massively infiltrated by lipid-laden macrophages

increased spleen weight ( J:48193 )

• at 8 to 10 weeks, spleen cellularity and weight is increased 5- to 7-fold

spleen hyperplasia ( J:48193 )

• mice exhibit splenomegaly with a 2- to 3-fold increase in cell counts

• at 8 to 10 weeks, spleen cellularity and weight is increased 5- to 7-fold

abnormal definitive hematopoiesis ( J:48193 )

• myeloid progenitor cells are increased

• following treatment with GM-CSF (granulocyte-macrophage colony stimulating factor) and IL-3 50% maximal colony formation is achieved at 10-fold lower concentrations compared to those for wild-type mice

• bone marrow cells are 2- to 3-fold more sensitive to SF (steel factor) and M-CSF (macrophage colony stimulating factor)

abnormal granulocyte differentiation ( J:48193 )

• there is an increase in granulocyte progenitor cells in the marrow

abnormal monocyte differentiation ( J:48193 )

• there is an increase in monocyte progenitor cells in the marrow

abnormal lymphopoiesis ( J:48193 )

• lymphoid progenitor cells are decreased

decreased bone marrow cell number ( J:48193 )

• progressive hypocellularity occurs

increased neutrophil cell number ( J:48193 )

• the percentage of circulating and bone marrow mature neutrophils is increased

decreased lymphocyte cell number ( J:48193 )

• the percentage of circulating lymphocytes is decreased

increased monocyte cell number ( J:48193 )

• the percentage of circulating monocytes is increased

respiratory system

abnormal lung morphology ( J:48193 )

• mice exhibit a uniform enlargement and patchy whitish discoloration of the pleural surfaces of the lung

• the air spaces are massively infiltrated by lipid-laden macrophages

growth/size/body

decreased body weight ( J:48193 )

• mice fail to thrive and exhibit a 17% reduction in body weight at 4 to 5 weeks of age and a further 5% decrease at 8 to 10 weeks compared to wild-type mice

increased spleen weight ( J:48193 )

• at 8 to 10 weeks, spleen cellularity and weight is increased 5- to 7-fold

spleen hyperplasia ( J:48193 )

• mice exhibit splenomegaly with a 2- to 3-fold increase in cell counts

• at 8 to 10 weeks, spleen cellularity and weight is increased 5- to 7-fold

immune system

abnormal granulocyte differentiation ( J:48193 )

• there is an increase in granulocyte progenitor cells in the marrow

abnormal monocyte differentiation ( J:48193 )

• there is an increase in monocyte progenitor cells in the marrow

abnormal macrophage chemotaxis ( J:48193 )

• the air spaces are massively infiltrated by lipid-laden macrophages

increased spleen weight ( J:48193 )

• at 8 to 10 weeks, spleen cellularity and weight is increased 5- to 7-fold

spleen hyperplasia ( J:48193 )

• mice exhibit splenomegaly with a 2- to 3-fold increase in cell counts

• at 8 to 10 weeks, spleen cellularity and weight is increased 5- to 7-fold

abnormal lymphopoiesis ( J:48193 )

• lymphoid progenitor cells are decreased

increased neutrophil cell number ( J:48193 )

• the percentage of circulating and bone marrow mature neutrophils is increased

decreased lymphocyte cell number ( J:48193 )

• the percentage of circulating lymphocytes is decreased

increased monocyte cell number ( J:48193 )

• the percentage of circulating monocytes is increased

cellular

abnormal granulocyte differentiation ( J:48193 )

• there is an increase in granulocyte progenitor cells in the marrow

abnormal monocyte differentiation ( J:48193 )

• there is an increase in monocyte progenitor cells in the marrow

abnormal macrophage chemotaxis ( J:48193 )

• the air spaces are massively infiltrated by lipid-laden macrophages

Genotype
MGI:3838993

cx4

• Allelic Composition: Il6^tm1Kopf/Il6^tm1Kopf; Inpp5d^tm1Rkh/Inpp5d^tm1Rkh
• Genetic Background: involves: 129 * C57BL/6

immune system

abnormal lymphopoiesis ( J:117320 )

• the percentage of prolymphocyte in the bone marrow is slightly less than wild-type (35% versus 27%)

decreased pro-B cell number ( J:117320 )

• the percentage of CD19⁺ B cell progenitors in the bone marrow is decreased by almost 4-fold

abnormal myelopoiesis ( J:117320 )

• 78% of mutant bone marrow cells are Mac-1⁺ compared to 56% in wild-type

hematopoietic system

abnormal lymphopoiesis ( J:117320 )

• the percentage of prolymphocyte in the bone marrow is slightly less than wild-type (35% versus 27%)

decreased pro-B cell number ( J:117320 )

• the percentage of CD19⁺ B cell progenitors in the bone marrow is decreased by almost 4-fold

abnormal myelopoiesis ( J:117320 )

• 78% of mutant bone marrow cells are Mac-1⁺ compared to 56% in wild-type

abnormal hematopoietic stem cell morphology ( J:117320 )

• there is a 2-fold decrease in Lin^-c-Kit^loSca-1^lo population in the bone marrow that contains the hematopoietic stem cell population

Genotype
MGI:3838991

cx5

• Allelic Composition: Inpp5d^tm1Rkh/Inpp5d^tm1Rkh; Rag1^tm1(GFP)Imku/Rag1⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA

hematopoietic system

abnormal lymphopoiesis ( J:117320 )

• there is a defect in development of early-lymphoid progenitors

• no GFP-positive cells are observed in the Lin^-c-Kit^hiSca-1⁺ cell population in the bone marrow compared 9% of the population being GFP-positive in Rag1^tm1(GFP)Imku heterozygotes

• there is a 10-fold decrease in Lin^-c-Kit^loSca-1^loGFP⁺ population in the bone marrow, corresponding to the prolymphocyte fraction

immune system

abnormal lymphopoiesis ( J:117320 )

• there is a defect in development of early-lymphoid progenitors

• no GFP-positive cells are observed in the Lin^-c-Kit^hiSca-1⁺ cell population in the bone marrow compared 9% of the population being GFP-positive in Rag1^tm1(GFP)Imku heterozygotes

• there is a 10-fold decrease in Lin^-c-Kit^loSca-1^loGFP⁺ population in the bone marrow, corresponding to the prolymphocyte fraction