Phenotypes Associated with This Genotype

Genotype
MGI:5467971

• Allelic Composition: Aldh2^{tm1a(EUCOMM)Wtsi}/Aldh2^{tm1a(EUCOMM)Wtsi}; Fancd2^tm1Hou/Fancd2^tm1Hou
• Genetic Background: involves: 129S4/SvJae * C57BL/6J * C57BL/6N

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

mortality/aging

increased susceptibility to xenobiotic induced morbidity/mortality ( J:193232 )

• fewer than expected mice are present at E16.5 following in utero exposure to ethanol at E7.5

premature death ( J:193232 )

• unexposed mice succumb to an acute illness (weight loss and lethargy) within 3 to 6 months

embryonic lethality during organogenesis ( J:193232 )

• despite expected ratios at E9.5, all offspring die by E13.5 when dams are Aldh2^{tm1a(EUCOMM)Wtsi} homozygotes despite no effect on offpsring heterozygous for the allele

immune system

abnormal thymus morphology ( J:188123 )

• the nucleated cellularity of the thymus is decreased in 8-12 week old mice

abnormal lymphopoiesis ( J:193232 )

• blast-like lymphoid cells in the peripheral blood film and bone marrow aspirate in unexposed mice

increased double-positive T cell number ( J:193232 )

• in three instances in unexposed mice

increased CD8-positive, alpha-beta T cell number ( J:193232 )

• in one instance in an unexposed mice

decreased leukocyte cell number ( J:188123 )

• in 8-12 week old mice

abnormal spleen morphology ( J:188123 )

• the nucleated cellularity of the spleen is decreased in 8-12 week old mice

enlarged spleen ( J:193232 )

• in unexposed mice

neoplasm

increased acute lymphoblastic leukemia incidence ( J:193232 )

• in unexposed mice

increased lymphoma incidence ( J:193232 )

• in most unexposed mice

increased T cell derived lymphoma incidence ( J:193232 )

• in some unexposed mice

growth/size/body

decreased body weight ( J:193232 )

• in unexposed mice

weight loss ( J:193232 )

• in unexposed mice

abnormal chest morphology ( J:193232 )

• most unexposed mice develop large mediastinal mass

enlarged spleen ( J:193232 )

• in unexposed mice

vision/eye

abnormal eye morphology ( J:193232 )

• unexposed mice exhibit eye abnormalities unlike control mice

• in utero exposure to ethanol increased the prevalence of eye abnormalities compared to in control mice

anophthalmia ( J:193232 )

• mice exposed to ethanol at E7.5 unlike control mice

nervous system

exencephaly ( J:193232 )

• mice exposed to ethanol at E7.5 unlike control mice

behavior/neurological

lethargy ( J:193232 )

• in unexposed mice

homeostasis/metabolism

increased susceptibility to xenobiotic induced morbidity/mortality ( J:193232 )

• fewer than expected mice are present at E16.5 following in utero exposure to ethanol at E7.5

increased physiological sensitivity to xenobiotic ( J:188123 )

• B cells, erythroid progenitor and granulocyte-macrophage progenitor cells are more sensitive to acetaldehyde than wild-type cells, but no more sensitive than single Fancd2 homozygotes

limbs/digits/tail

kinked tail ( J:193232 )

• in unexposed mice

hematopoietic system

abnormal thymus morphology ( J:188123 )

• the nucleated cellularity of the thymus is decreased in 8-12 week old mice

abnormal lymphopoiesis ( J:193232 )

• blast-like lymphoid cells in the peripheral blood film and bone marrow aspirate in unexposed mice

increased double-positive T cell number ( J:193232 )

• in three instances in unexposed mice

extramedullary hematopoiesis ( J:188123 )

• aged mice that do not develop leukemia show extramedullary hematopoiesis

anemia ( J:188123 , J:193232 )

• aged mice that do not develop leukemia spontaneously develop aplastic anemia, with accumulation of damaged DNA within the hematopoietic stem and progenitor cell pool (J:188123)

• in 6 to 8 week old mice exposed to ethanol (J:193232)

impaired hematopoiesis ( J:193232 )

• almost complete obliteration of bone marrow hematopoiesis in 6 to 8 week old mice exposed to ethanol

abnormal bone marrow cell morphology/development ( J:193232 )

• from bone marrow of 6 to 8 week old mice exposed to ethanol produces fewer progenitor colony-forming units corresponding to pre-B cells, granulocytes and erythrocytes compared with control mice

decreased bone marrow cell number ( J:188123 , J:193232 )

• the nucleated cellularity of whole bone marrow is decreased in 8-12 week old mice (J:188123)

• of nucleated cells in 6 to 8 week old mice exposed to ethanol (J:193232)

decreased erythrocyte cell number ( J:188123 , J:193232 )

• in 8-12 week old mice (J:188123)

• young mice, however exhibit normal T cell, B cell, myeloid, and erythroid differentiation (J:188123)

• in 6 to 8 week old mice exposed to ethanol (J:193232)

decreased hematocrit ( J:188123 )

• in 8-12 week old mice

decreased hemoglobin content ( J:188123 , J:193232 )

• in 8-12 week old mice (J:188123)

• in 6 to 8 week old mice exposed to ethanol (J:193232)

increased mean corpuscular volume ( J:188123 )

• young mice exhibit an increase in the mean corpuscular volume of erythrocytes

thrombocytopenia ( J:188123 )

• in 8-12 week old mice

increased CD8-positive, alpha-beta T cell number ( J:193232 )

• in one instance in an unexposed mice

decreased leukocyte cell number ( J:188123 )

• in 8-12 week old mice

decreased hematopoietic stem cell number ( J:188123 )

• young mice that have not develop leukemia show a 30-fold reduction in the LKS population, 10-fold reduction in the frequency of LT-HSCs (Lin- c-Kit+ Sca-1+ Flt3- CD34-), and a 251-fold reduction in the frequency of HSCs (Lin- CD41- CD48- CD150+ c-Kit+ Sca-1+) in the bone marrow

pancytopenia ( J:188123 )

• aged mice that do not develop leukemia show pancytopenia

abnormal spleen morphology ( J:188123 )

• the nucleated cellularity of the spleen is decreased in 8-12 week old mice

enlarged spleen ( J:193232 )

• in unexposed mice

abnormal hematopoietic stem cell physiology ( J:188123 )

• accumulation in the S-G2-M phase of the cell cycle in long term hematopoietic stem cells (LT-HSCs)

• reduction in the number of quiescent (G0) LT-HSCs, with the majority actively cycling

endocrine/exocrine glands

abnormal thymus morphology ( J:188123 )

• the nucleated cellularity of the thymus is decreased in 8-12 week old mice

increased T cell derived lymphoma incidence ( J:193232 )

• in some unexposed mice

cellular

increased sensitivity to induced cell death ( J:188123 )

• B cells, erythroid progenitor and granulocyte-macrophage progenitor cells are more sensitive to acetaldehyde than wild-type cells, but no more sensitive than single Fancd2 homozygotes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Fanconi anemia complementation group D2		DOID:0111083	OMIM:227646	J:193232