Phenotypes Associated with This Genotype

Genotype
MGI:2175773

• Allelic Composition: Cdkn2c^tm1Bbd/Cdkn2c^tm1Bbd
• Genetic Background: involves: 129S1/Sv * C57BL/6

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

mortality/aging

decreased tumor-free survival time ( J:63299 )

• about 40% die before 18 months of age due to large pituitary tumors

neoplasm

neoplasm ( J:102702 )

N • mice irradiated with 4 Gy at P5 or P6 do not develop cerebellar tumors

increased pheochromocytoma incidence ( J:63299 )

• 10% incidence of pheochromocytomas

increased pituitary adenoma incidence ( J:63299 )

• most large pituitary tumors are chromophobe adenomas of the pars intermedia

increased T cell derived lymphoma incidence ( J:63299 )

• low incidence of thymic lymphoma

increased testis tumor incidence ( J:63299 )

♂ • 12% incidence of testicular neoplasia

increased B cell derived lymphoma incidence ( J:63299 )

• low incidence of B-cell lymphoma

increased renal carcinoma incidence ( J:63299 )

• low incidence of renal cell carcinoma

increased hemangiosarcoma incidence ( J:63299 )

• low incidence of angiosarcoma

endocrine/exocrine glands

increased pheochromocytoma incidence ( J:63299 )

• 10% incidence of pheochromocytomas

pituitary gland hyperplasia ( J:63299 )

• seen as early as 6 months of age

increased pituitary adenoma incidence ( J:63299 )

• most large pituitary tumors are chromophobe adenomas of the pars intermedia

increased T cell derived lymphoma incidence ( J:63299 )

• low incidence of thymic lymphoma

abnormal mammary gland epithelium morphology ( J:63299 )

♀ • cysts in the galactophor ducts of the mammary epithelium at 12 weeks of age

mammary gland hyperplasia ( J:63299 )

♀

abnormal Leydig cell differentiation ( J:68829 )

♂ • failure to differentiate, not associated with abnormal levels of luteinizing hormone (LH)

increased Leydig cell number ( J:68829 )

♂

enlarged testis ( J:68829 )

♂

increased testis tumor incidence ( J:63299 )

♂ • 12% incidence of testicular neoplasia

growth/size/body

kidney cyst ( J:63299 )

• tubular and glomerular cysts

kidney cortex cyst ( J:63299 )

increased body size ( J:63299 )

increased body weight ( J:63299 )

• weight about 20% more than wild-type mice

enlarged spleen ( J:63299 )

• evident after 6 months of age

hematopoietic system

increased T cell derived lymphoma incidence ( J:63299 )

• low incidence of thymic lymphoma

enlarged spleen ( J:63299 )

• evident after 6 months of age

increased spleen white pulp amount ( J:63299 )

• cellular expansion of the white pulp

immune system

increased T cell derived lymphoma incidence ( J:63299 )

• low incidence of thymic lymphoma

enlarged spleen ( J:63299 )

• evident after 6 months of age

increased spleen white pulp amount ( J:63299 )

• cellular expansion of the white pulp

abnormal lymph node medulla morphology ( J:63299 )

• cellular expansion of plasma cells in the medulla

enlarged lymph nodes ( J:63299 )

lymphoid hyperplasia ( J:63299 )

• lymphoproliferative expansion, most often seen in the kidneys, lung, liver, and salivary glands

nervous system

abnormal neuron differentiation ( J:102702 )

• GNPs from mutants show ~50% levels of proliferation compared to Cdkn2c, Trp53-double null cells after 3 days in culture and levels of cells incorporating BrdU are still less in single mutants in tests where cells are stimulated with Shh after culture

abnormal neuronal migration ( J:102702 )

• presence of these aberrant foci cerebellar molecular layer in mutants indicates a migration defect

pituitary gland hyperplasia ( J:63299 )

• seen as early as 6 months of age

increased pituitary adenoma incidence ( J:63299 )

• most large pituitary tumors are chromophobe adenomas of the pars intermedia

abnormal cerebellar molecular layer ( J:102702 )

• when irradiated mice are sacrificed at 6 months of age, all mice have abnormal microscopic foci of neuronal cells that are positive for GABA(A) alpha6 receptor subunit, a marker of differentiated, post-mitotic granule neurons which is not seen in granule neuronal precursor cells; these cells are not proliferating

• when mice are exposed to 4 Gy at P5 and sacrificed at P30, all show ~3-fold more neuronal foci (neuronal nests) located more deeply in the molecular layer compared to few detected accumulating at the external surface of the molecular layer in treated wild type

reproductive system

abnormal Leydig cell differentiation ( J:68829 )

♂ • failure to differentiate, not associated with abnormal levels of luteinizing hormone (LH)

increased Leydig cell number ( J:68829 )

♂

enlarged testis ( J:68829 )

♂

increased testis tumor incidence ( J:63299 )

♂ • 12% incidence of testicular neoplasia

renal/urinary system

kidney cyst ( J:63299 )

• tubular and glomerular cysts

kidney cortex cyst ( J:63299 )

increased renal carcinoma incidence ( J:63299 )

• low incidence of renal cell carcinoma

cortical renal glomerulopathies ( J:63299 )

• about 30% of mutants show cortical glomerulopathies after 9 months of age

• atropic glomeruli and glomerular cysts are sometimes seen

cellular

abnormal apoptosis ( J:68829 )

• increased germ cell apoptosis

abnormal neuron differentiation ( J:102702 )

• GNPs from mutants show ~50% levels of proliferation compared to Cdkn2c, Trp53-double null cells after 3 days in culture and levels of cells incorporating BrdU are still less in single mutants in tests where cells are stimulated with Shh after culture

abnormal neuronal migration ( J:102702 )

• presence of these aberrant foci cerebellar molecular layer in mutants indicates a migration defect

homeostasis/metabolism

decreased circulating testosterone level ( J:68829 )

• ~75% reduction in levels relative to wild-type

• associated with a failure of leydig cell differentiation

integument

abnormal mammary gland epithelium morphology ( J:63299 )

♀ • cysts in the galactophor ducts of the mammary epithelium at 12 weeks of age

mammary gland hyperplasia ( J:63299 )

♀