Phenotypes associated with this allele

• Allele Symbol: Lmna^tm1.1Otin
• Allele Name: targeted mutation 1.1, Carlos Lopez-Otin
• Allele ID: MGI:5295747
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Lmna^tm1.1Otin/Lmna^tm1.1Otin	involves: 129P2/OlaHsd * C57BL/6	MGI:5295749
hm2	Lmna^tm1.1Otin/Lmna^tm1.1Otin	involves: 129P2/OlaHsd * C57BL/6NTac	MGI:7311570
ht3	Lmna^tm1.1Otin/Lmna^+	involves: 129P2/OlaHsd * C57BL/6	MGI:5295754
ht4	Lmna^tm1.1Otin/Lmna^+	involves: 129P2/OlaHsd * C57BL/6NTac	MGI:7311569
cx5	Lmna^tm1.1Otin/Lmna^tm1.1Otin Nat10^tm1a(KOMP)Wtsi/Nat10^+	involves: 129P2/OlaHsd * C57BL/6NTac	MGI:7311572
cx6	Lmna^tm1.1Otin/Lmna^+ Nat10^tm1a(KOMP)Wtsi/Nat10^+	involves: 129P2/OlaHsd * C57BL/6NTac	MGI:7311574

Genotype
MGI:5295749

hm1

• Allelic Composition: Lmna^tm1.1Otin/Lmna^tm1.1Otin
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

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

mortality/aging

premature death ( J:177575 , J:177632 )

• mutants exhibit an average lifespan of 103 days (J:177632)

premature aging ( J:177632 )

• mutants exhibit premature aging as indicated by an increase in senescence-associated beta-galactosidase staining in the liver and kidney at 3 months of age

growth/size/body

small lower incisors ( J:177632 )

• smaller lower incisors

weight loss ( J:177632 )

• mutants exhibit progressive weight loss after 3 weeks of age

postnatal growth retardation ( J:177632 )

• mutants show reduced growth rates after 3 weeks of age, with progressive weight loss

reproductive system

infertility ( J:177632 )

cardiovascular system

calcified aorta ( J:211388 )

♂ • seen in 10 week old mice

♂ • treatment with intraperitoneal injections of pyrophosphate over 9 weeks inhibits aortic calcification

vascular smooth muscle hypoplasia ( J:177632 )

• mutants exhibit loss of vascular smooth muscle cells in the aortic arch, but not in the medial layer of the thoracic aorta

decreased heart rate ( J:177632 )

• blood pressure appears normal but mutants progressively develop bradycardia between 9 and 15 weeks of age

prolonged QRS complex duration ( J:177632 )

• ECG indicates prolonged QRS waves without changes in the PR interval, indicating altered heart ventricular depolarization

• however, no differences in systolic function or diastolic function are seen

cellular

abnormal cell nucleus morphology ( J:177575 , J:177632 )

• MEFs have more misshapen nuclei with nuclear blebs than wild-type MEFs (J:177575)

• mutants show nuclear abnormalities due to progerin accumulation (J:177632)

• 81% of cultured fibroblasts at passage 5 contain large and abnormally shaped nuclei (J:177632)

abnormal cell physiology ( J:177632 )

• 81% of cultured fibroblasts at passage 5 contain large and abnormally shaped nuclei with foci highly stained with anti-gammaH2AX antibodies, indicating genotoxic stress

craniofacial

small cranium ( J:177632 )

• skulls are reduced in size

small lower incisors ( J:177632 )

• smaller lower incisors

adipose tissue

decreased subcutaneous adipose tissue amount ( J:177632 )

• older mutants exhibit a generalized loss of principal fat deposits, with a loss of the subcutaneous fat layer

homeostasis/metabolism

abnormal blood homeostasis ( J:177632 )

• mutants show a decrease in serum levels of insulin-like factor 1

hypoglycemia ( J:177632 )

• at 2 months of age, mutants show a decrease in serum glucose concentrations that leads to extreme hypoglycemia by 3 months of age

decreased circulating insulin level ( J:177632 )

decreased circulating leptin level ( J:177632 )

increased circulating growth hormone level ( J:177632 )

increased circulating adiponectin level ( J:177632 )

immune system

small thymus ( J:177632 )

• thymus exhibits a marked involution relative to wild-type mice, even after accounting for body size differences

small spleen ( J:177632 )

• spleen exhibits a marked involution relative to wild-type mice, even after accounting for body size differences

integument

decreased subcutaneous adipose tissue amount ( J:177632 )

• older mutants exhibit a generalized loss of principal fat deposits, with a loss of the subcutaneous fat layer

abnormal hair follicle morphology ( J:177632 )

• older mutants exhibit attrition of hair follicles

behavior/neurological

decreased grip strength ( J:177632 )

muscle

vascular smooth muscle hypoplasia ( J:177632 )

• mutants exhibit loss of vascular smooth muscle cells in the aortic arch, but not in the medial layer of the thoracic aorta

hematopoietic system

small thymus ( J:177632 )

• thymus exhibits a marked involution relative to wild-type mice, even after accounting for body size differences

small spleen ( J:177632 )

• spleen exhibits a marked involution relative to wild-type mice, even after accounting for body size differences

skeleton

small cranium ( J:177632 )

• skulls are reduced in size

small lower incisors ( J:177632 )

• smaller lower incisors

lordokyphosis ( J:177632 )

• mutants develop cervicothoracic lordokyphosis

abnormal bone structure ( J:177632 )

• tibias exhibit increased porosity

decreased bone mineral density ( J:177632 )

• tibias exhibit reduced bone density

decreased bone volume ( J:177632 )

• bone volume of tibias is decreased

decreased compact bone thickness ( J:177632 )

• tibias exhibit reduced cortical thickness

decreased bone trabecula number ( J:177632 )

endocrine/exocrine glands

small thymus ( J:177632 )

• thymus exhibits a marked involution relative to wild-type mice, even after accounting for body size differences

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progeria		DOID:3911	OMIM:176670	J:177575 , J:177632 , J:211388

Genotype
MGI:7311570

hm2

• Allelic Composition: Lmna^tm1.1Otin/Lmna^tm1.1Otin
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6NTac

mortality/aging

premature death ( J:261974 )

reproductive system

oligozoospermia ( J:261974 )

penis prolapse ( J:261974 )

♂

female infertility ( J:261974 )

♀ • due to reduced reproductive fitness

♀ • however, normal oocyte production and fertilization with wild-type sperm

reduced male fertility ( J:261974 )

♂

adipose tissue

decreased subcutaneous adipose tissue amount ( J:261974 )

• treatment with Remodelin partially rescues phenotype

cardiovascular system

abnormal aorta tunica adventitia morphology ( J:261974 )

• increased thickness that is partially rescued by Remodelin treatment

decreased heart rate ( J:261974 )

growth/size/body

decreased body weight ( J:261974 )

immune system

keratoconjunctivitis sicca ( J:261974 )

renal/urinary system

penis prolapse ( J:261974 )

♂

skeleton

kyphosis ( J:261974 )

vision/eye

keratoconjunctivitis sicca ( J:261974 )

cellular

oligozoospermia ( J:261974 )

integument

decreased subcutaneous adipose tissue amount ( J:261974 )

• treatment with Remodelin partially rescues phenotype

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progeria		DOID:3911	OMIM:176670	J:261974

Genotype
MGI:5295754

ht3

• Allelic Composition: Lmna^tm1.1Otin/Lmna⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

mortality/aging

premature death ( J:177575 , J:177632 )

• mutants exhibit an average lifespan of 242 days (J:177632)

growth/size/body

weight loss ( J:177632 )

• mutants start to lose weight at around 8 months of age

homeostasis/metabolism

abnormal blood homeostasis ( J:211388 )

• 8-fold decrease in plasma ATP concentrations

• 9-fold decrease in plasma pyrophosphate concentrations

• however, no differences in plasma phosphorus or calcium levels are seen

decreased circulating glucose level ( J:177632 )

• at 8 months of age, heterozygotes show a decrease in serum glucose concentrations

increased circulating alkaline phosphatase level ( J:211388 )

• 29.5% higher levels of plasma alkaline phosphatase activity than controls

cellular

abnormal cell nucleus morphology ( J:177575 , J:177632 )

• MEFs have more misshapen nuclei with nuclear blebs than wild-type MEFs (J:177575)

• mutants show nuclear abnormalities due to progerin accumulation (J:177632)

cardiovascular system

calcified aorta ( J:211388 )

• medial calcification in aortic arch and thoracic aorta at 30-34 weeks of age

calcified thoracic aorta ( J:211388 )

calcified aortic arch ( J:211388 )

abnormal vascular smooth muscle physiology ( J:211388 )

• primary cultures of vascular smooth muscle cells from aortic tissue show a lower capacity to inhibit calcium deposition than control cells when incubated in calcifying medium

• aortic vascular smooth cells exhibit impaired capacity to synthesize extracellular pyrophosphate, show lower levels of extracellular ATP and intracellular ATP indicating impaired ATP synthesis, and have a lower COX:CS ratio indicating impaired mitochondrial function

muscle

abnormal vascular smooth muscle physiology ( J:211388 )

• primary cultures of vascular smooth muscle cells from aortic tissue show a lower capacity to inhibit calcium deposition than control cells when incubated in calcifying medium

• aortic vascular smooth cells exhibit impaired capacity to synthesize extracellular pyrophosphate, show lower levels of extracellular ATP and intracellular ATP indicating impaired ATP synthesis, and have a lower COX:CS ratio indicating impaired mitochondrial function

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progeria		DOID:3911	OMIM:176670	J:211388

Genotype
MGI:7311569

ht4

• Allelic Composition: Lmna^tm1.1Otin/Lmna⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6NTac

mortality/aging

premature aging ( J:261974 )

• premature aging as in homozygotes with delayed onset

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progeria		DOID:3911	OMIM:176670	J:261974

Genotype
MGI:7311572

cx5

• Allelic Composition: Lmna^tm1.1Otin/Lmna^tm1.1Otin; Nat10^{tm1a(KOMP)Wtsi}/Nat10⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6NTac

mortality/aging

premature death ( J:261974 )

• delayed compared to mice homozygous for the Lmna^tm1.1Otin and wild-type Nat10

reproductive system

reproductive system phenotype ( J:261974 )

N • unlike mice homozygous for the Lmna^tm1.1Otin, mice do not exhibit penis prolapse

reduced fertility ( J:261974 )

• partially rescued compared to mice homozygous for the Lmna^tm1.1Otin and wild-type Nat10

skeleton

kyphosis ( J:261974 )

• delayed compared to mice homozygous for the Lmna^tm1.1Otin and wild-type Nat10

vision/eye

vision/eye phenotype ( J:261974 )

N • unlike mice homozygous for the Lmna^tm1.1Otin, mice do not exhibit keratoconjunctivitis sicca

cardiovascular system

decreased heart rate ( J:261974 )

• delayed onset

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progeria		DOID:3911	OMIM:176670	J:261974

Genotype
MGI:7311574

cx6

• Allelic Composition: Lmna^tm1.1Otin/Lmna⁺; Nat10^{tm1a(KOMP)Wtsi}/Nat10⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6NTac

mortality/aging

premature death ( J:261974 )

• significantly delayed compared to in Lmna^tm1.1Otin homozygotes

skeleton

kyphosis ( J:261974 )

• significantly delayed compared to in Lmna^tm1.1Otin homozygotes

growth/size/body

decreased body weight ( J:261974 )

• significantly delayed compared to in Lmna^tm1.1Otin homozygotes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progeria		DOID:3911	OMIM:176670	J:261974