Phenotypes associated with this allele

• Allele Symbol: Hat1^tm1.1Mrpa
• Allele Name: targeted mutation 1.1, Mark R Parthun
• Allele ID: MGI:5523519
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Hat1^tm1.1Mrpa/Hat1^tm1.1Mrpa	B6.Cg-Hat1^tm1.1Mrpa	MGI:7336043
hm2	Hat1^tm1.1Mrpa/Hat1^tm1.1Mrpa	involves: C57BL/6J	MGI:5523520
ht3	Hat1^tm1.1Mrpa/Hat1^+	B6.Cg-Hat1^tm1.1Mrpa	MGI:7336042

Genotype
MGI:7336043

hm1

• Allelic Composition: Hat1^tm1.1Mrpa/Hat1^tm1.1Mrpa
• Genetic Background: B6.Cg-Hat1^tm1.1Mrpa

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

cellular

disorganized mitochondrial cristae ( J:296531 )

• MEFs exhibit mitochondria with disorganized cristae that have an open structure

increased mitochondrial size ( J:296531 )

• MEFs exhibit defective enlarged mitochondria

decreased fibroblast proliferation ( J:296531 )

• when incubated in glucosefree media supplemented with galactose over a 5day period, MEFs grow poorly on galactose whereas wildtype MEFs show a >20fold increase in cell proliferation by day 5

early cellular replicative senescence ( J:296531 )

• in culture, primary mouse embryonic fibroblasts (MEFs) show significant levels of senescence at passage 1 (~5%) that increase to ~35% by passage 7 and accumulate high levels of p21

abnormal double-strand DNA break repair ( J:296531 )

• MEFs exhibit a marked increase in DNA doublestrand breaks, as measured by comet assays

• untreated MEFs show an ~5-fold increase in the % of gammaH2AX+ cells relative to wild-type MEFs

• however, after incubation with antioxidant Nacetylcysteine (NAC), % of gammaH2AX+ cells is comparable to that in NAC-treated wild-type MEFs

abnormal mitochondrial physiology ( J:296531 )

• MEFs show loss of mitochondrial membrane potential, as measured by fluorescence microscopy after JC1 staining: MEFs emit largely green fluorescence indicative of mitochondrial depolarization, whereas wild-type MEFs are predominantly red

• MEFs show a lower basal oxygen consumption rate (OCR) and a decreased maximal respiratory capacity

oxidative stress ( J:296531 )

• MEFs exhibit an ~2-fold increase in basal levels of reactive oxygen species (ROS) relative to wild-type MEFs

homeostasis/metabolism

abnormal double-strand DNA break repair ( J:296531 )

• MEFs exhibit a marked increase in DNA doublestrand breaks, as measured by comet assays

• untreated MEFs show an ~5-fold increase in the % of gammaH2AX+ cells relative to wild-type MEFs

• however, after incubation with antioxidant Nacetylcysteine (NAC), % of gammaH2AX+ cells is comparable to that in NAC-treated wild-type MEFs

Genotype
MGI:5523520

hm2

• Allelic Composition: Hat1^tm1.1Mrpa/Hat1^tm1.1Mrpa
• Genetic Background: involves: C57BL/6J

Skeletal defects in Hat1^tm1.1Mrpa/Hat1^tm1.1Mrpa mice

mortality/aging

perinatal lethality, complete penetrance ( J:199077 )

• mice either are born dead or die shortly after birth

neonatal lethality, complete penetrance ( J:199077 )

• mice either are born dead or die shortly after birth

prenatal lethality, incomplete penetrance ( J:199077 )

• fewer than expected mice are born

respiratory system

abnormal nose morphology ( J:199077 )

• the nasal passage is often missing, often overgrown with bone, in some mice

abnormal lung development ( J:199077 )

• mice exhibit immature fetal lungs as determined by more cells per alveolar septum, vascularity, aerated lung tissue and septum thickness compared with wild-type mice

thick lung-associated mesenchyme ( J:199077 )

abnormal lung interstitium morphology ( J:199077 )

• increased cell proliferation at E11.5 and in neonates

primary atelectasis ( J:199077 )

thick pulmonary interalveolar septum ( J:199077 )

abnormal respiratory system physiology ( J:199077 )

• increased cell proliferation of lung interstitial cells at E11.5 and in neonates

respiratory failure ( J:199077 )

skeleton

abnormal cranium morphology ( J:199077 )

• in some mice

abnormal mandible morphology ( J:199077 )

• fused into a single bone in some neonates

absent mandible ( J:199077 )

• in some neonates

abnormal vertebrae morphology ( J:199077 )

• degenerate near the base of the spinal column

increased bone mineral density ( J:199077 )

• with reduced cartilage staining in the skull

cellular

abnormal mitosis ( J:199077 )

• moderate accumulation of mouse embryonic fibroblasts in the G2/M

decreased fibroblast proliferation ( J:199077 )

• in mouse embryonic fibroblasts

growth/size/body

abnormal nose morphology ( J:199077 )

• the nasal passage is often missing, often overgrown with bone, in some mice

decreased birth body size ( J:199077 )

craniofacial

abnormal craniofacial morphology ( J:199077 )

• in some mice

abnormal cranium morphology ( J:199077 )

• in some mice

abnormal mandible morphology ( J:199077 )

• fused into a single bone in some neonates

absent mandible ( J:199077 )

• in some neonates

abnormal nose morphology ( J:199077 )

• the nasal passage is often missing, often overgrown with bone, in some mice

Genotype
MGI:7336042

ht3

• Allelic Composition: Hat1^tm1.1Mrpa/Hat1⁺
• Genetic Background: B6.Cg-Hat1^tm1.1Mrpa

mortality/aging

premature death ( J:296531 )

• mice exhibit an average lifespan of 69.1 weeks; over a period of 120 weeks, 92% of mice died versus only 9% of wild-type controls

• ~40% of mice die spontaneously (cause indeterminate due to tissue lysis)

premature aging ( J:296531 )

• mice exhibit an array of phenotypes that are consistent with earlyonset aging

growth/size/body

decreased birth body size ( J:296531 )

• body size is reduced at birth; however, body size is normalized by 5 weeks of age

decreased body weight ( J:296531 )

• mice surviving to 80 weeks show a marked decrease in body weight

weight loss ( J:296531 )

• mice begin to exhibit weight loss after 40 weeks of age

skeleton

lordokyphosis ( J:296531 )

• 14.6% of mice exhibit lordokyphosis at the time of death

• 5.2% of mice exhibit lordokyphosis plus tumors at the time of death

• 8.3% of mice exhibit lordokyphosis plus hindlimb paralysis at the time of death

adipose tissue

decreased subcutaneous adipose tissue amount ( J:296531 )

• all mice sacrificed between 54 and 80 weeks of age exhibit an almost complete lack of subcutaneous fat tissue

decreased abdominal adipose tissue amount ( J:296531 )

• 1 of 3 mice sacrificed between 54 and 80 weeks of age show visceral fat depletion

decreased total body fat amount ( J:296531 )

• mice exhibit a trend towards decreased total body fat, as measured by EchoMRI

decreased fat cell size ( J:296531 )

• adipocytes are significantly smaller, indicating fat depletion

muscle

decreased skeletal muscle mass ( J:296531 )

• at 54 weeks of age, quadriceps muscles show a significant loss of muscle mass

muscle degeneration ( J:296531 )

• 5.2% of mice exhibit muscle degeneration/atrophy at the time of death

skeletal muscle degeneration ( J:296531 )

• 2 of 3 mice sacrificed between 54 and 80 weeks of age show moderate skeletal muscle vacuolation (degeneration)

muscular atrophy ( J:296531 )

• 5.2% of mice exhibit muscle degeneration/atrophy at the time of death

skeletal muscle atrophy ( J:296531 )

• at 54 weeks of age, quadriceps muscles show increased mRNA levels of muscle atrophy markers Fbxo32 (F-box protein 32, aka MAFbx) and Trim63 (tripartite motif-containing 63, aka MuRF1)

neoplasm

increased tumor incidence ( J:296531 )

• 8.3% of mice exhibit tumors at the time of death; tumors are found primarily in the liver, spleen, and kidney

• 5.2% of mice exhibit lordokyphosis plus tumors at the time of death

increased liver tumor incidence ( J:296531 )

increased histiocytic sarcoma incidence ( J:296531 )

• 50% of mice sacrificed between 54 and 80 weeks of age show histiocytic sarcoma in the liver while 33% of mice show histiocytic sarcoma in spleen

increased spleen neoplasm incidence ( J:296531 )

increased kidney tumor incidence ( J:296531 )

behavior/neurological

hindlimb paralysis ( J:296531 )

• 6.25% of mice exhibit hindlimb paralysis at the time of death

• 8.3% of mice exhibit lordokyphosis plus hindlimb paralysis at the time of death

cardiovascular system

abnormal interventricular septum morphology ( J:296531 )

• 1 of 3 mice sacrificed between 54 and 80 weeks of age show interventricular septum degeneration

integument

decreased subcutaneous adipose tissue amount ( J:296531 )

• all mice sacrificed between 54 and 80 weeks of age exhibit an almost complete lack of subcutaneous fat tissue

cellular

early cellular replicative senescence ( J:296531 )

• in culture, primary mouse embryonic fibroblasts (MEFs) undergo early senescence and accumulate high levels of p21

abnormal double-strand DNA break repair ( J:296531 )

• MEFs exhibit a modest but statistically significant increase in DNA doublestrand breaks, as measured by comet assays

oxidative stress ( J:296531 )

• MEFs exhibit an ~2-fold increase in basal levels of reactive oxygen species (ROS) relative to wild-type MEFs

homeostasis/metabolism

abnormal double-strand DNA break repair ( J:296531 )

• MEFs exhibit a modest but statistically significant increase in DNA doublestrand breaks, as measured by comet assays

liver/biliary system

increased liver tumor incidence ( J:296531 )

renal/urinary system

increased kidney tumor incidence ( J:296531 )