Phenotypes Associated with This Genotype

Genotype
MGI:2654873

• Allelic Composition: Thra^tm2Ven/Thra^tm2Ven
• Genetic Background: involves: 129P2/OlaHsd * BALB/c

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

mortality/aging

perinatal lethality, incomplete penetrance ( J:72959 )

• at birth, the % of surviving pups obtained from heterozygous intercrosses may not display a Mendelian distribution, depending on environmental factors

endocrine/exocrine glands

abnormal thyroid follicle morphology ( J:72959 )

• adult homozygotes show a general disorganization of the thyroid follicles and flattening of the epithelium, as shown by uneven follicle sizes and reduced interstitial spaces

• however, no goiter is detected up to >18 months of age

abnormal thyroid gland physiology ( J:72959 )

• in response to TSH injections, homozygotes display reduced increases of free T3 and T4 serum levels relative to wild-type mice

• notably, homozygotes exhibit a mixed hyper- and hypothyroid phenotype, dependent on the tissue studied

decreased activity of thyroid gland ( J:72959 )

• homozygotes show signs of hypothyroidism, including significantly reduced levels of free T3 T4, poor responses to TSH, increased fat content, and skeletal defects associated with a late-onset growth retardation

increased activity of thyroid gland ( J:72959 )

• in addition to hypothyroidism, homozygotes display features of hyperthyroidism, including reduced body weight, elevated heart rate, and increased body temperature

homeostasis/metabolism

decreased circulating thyroxine level ( J:72959 )

• both male and female homozygotes show significantly reduced free T4 levels in serum relative to wild-type littermates

decreased circulating triiodothyronine level ( J:72959 )

• both male and female homozygotes show significantly reduced free T3 levels in serum relative to wild-type littermates

• total T3 levels are significantly reduced only in female homozygotes

decreased circulating insulin-like growth factor I level ( J:72959 )

• homozygotes display significantly reduced serum levels of IGF-I relative to wild-type mice

increased body temperature ( J:72959 )

• homozygotes display an increased body temperature (36.9 0.1 C) relative to wild-type mice (36.5 0.1 C)

abnormal thyroid-stimulating hormone level ( J:72959 )

• at 6-20 weeks, both male and female homozygotes display inappropriately normal serum levels of TSH, suggesting an alteration in the pituitary-thyroid axis

growth/size/body

decreased body weight ( J:72959 )

• both female and male homozygotes show a slightly reduced body weight from birth to adulthood relative to wild-type mice

obese ( J:72959 )

• adult homozygotes are obese

postnatal growth retardation ( J:72959 )

• both female and male homozygotes show a slightly delayed growth spurt during the first 9 weeks of life relative to wild-type mice

skeleton

abnormal osteoclast physiology ( J:72959 )

• homozygotes display a 57% reduction in osteoclast activity relative to wild-type mice

• in contrast, serum levels of osteocalcin, a marker of bone formation, remain unaffected

decreased bone mineral content ( J:72959 )

• homozygotes show a significant reduction in areal bone mineral (BM) content of the femur and L6 vertebrae relative to wild-type mice

decreased areal bone mineral density ( J:72959 )

• homozygotes show a significant reduction in areal bone mineral (BM) density of the femur and L6 vertebrae relative to wild-type mice

• however, no delay in the mineralization of the epiphysis is observed

abnormal compact bone morphology ( J:72959 )

• homozygotes exhibit decreased tibial cortical bone mineral content relative to wild-type mice

• however, no significant reduction in longitudinal bone growth is observed, such that tibias and femurs are of normal length

decreased compact bone area ( J:72959 )

• homozygotes exhibit decreased tibial cortical bone periosteal and endosteal circumferences, and cortical area relative to wild-type mice

abnormal trabecular bone morphology ( J:72959 )

• homozygotes display decreased trabecular bone mineral density (BMD), as shown by a 24% reduction in proximal tibia

adipose tissue

increased total body fat amount ( J:72959 )

• homozygotes exhibit a significant increase in fat content (121%) relative to wild-type mice

• however, serum levels of corticosterone and leptin are not significantly altered

reproductive system

prolonged estrous cycle ( J:72959 )

♀ • female homozygotes display a slightly prolonged estrous cycle, suggesting aberrant ovulation

reduced female fertility ( J:72959 )

♀ • female homozygotes generally fail to conceive

♀ • female homozygotes display partial fertility but only under optimized animal care conditions

♀ • homozygous intercrosses rarely generate litters

♀ • Background Sensitivity: breeding abnormalities are exacerbated after the mutation is backcrossed for two generations onto the C57BL/6J background

behavior/neurological

abnormal pup retrieval ( J:72959 )

♀ • if pups are born, female homozygotes fail to rear their offspring

cardiovascular system

increased heart rate ( J:72959 )

• homozygotes display a 10% increase in basal heart rate relative to wild-type littemates, despite their lower serum T3 levels

immune system

abnormal osteoclast physiology ( J:72959 )

• homozygotes display a 57% reduction in osteoclast activity relative to wild-type mice

• in contrast, serum levels of osteocalcin, a marker of bone formation, remain unaffected

hematopoietic system

abnormal osteoclast physiology ( J:72959 )

• homozygotes display a 57% reduction in osteoclast activity relative to wild-type mice

• in contrast, serum levels of osteocalcin, a marker of bone formation, remain unaffected