Phenotypes associated with this allele

• Allele Symbol: Lmna⁺
• Allele Name: wild type
• Allele ID: MGI:2431226
• Summary: 22 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
ht1	Lmna^Dhe/Lmna^+	B6(D2)-Lmna^Dhe/TyGrsrJ	MGI:4459466
ht2	Lmna^em1Fenz/Lmna^+	C57BL/6-Lmna^em1Fenz	MGI:7518590
ht3	Lmna^tm1b(EUCOMM)Wtsi/Lmna^+	C57BL/6N-Lmna^tm1b(EUCOMM)Wtsi/Ics	MGI:5757315
ht4	Lmna^tm2.1Gbon/Lmna^+	involves: 129 * C57BL/6	MGI:5906504
ht5	Lmna^tm4Lgf/Lmna^+	involves: 129P2/OlaHsd * C57BL/6	MGI:3837138
ht6	Lmna^tm1.1Otin/Lmna^+	involves: 129P2/OlaHsd * C57BL/6	MGI:5295754
ht7	Lmna^tm1Lgf/Lmna^+	involves: 129P2/OlaHsd * C57BL/6	MGI:3817506
ht8	Lmna^tm11Lgf/Lmna^+	involves: 129P2/OlaHsd * C57BL/6	MGI:5754489
ht9	Lmna^tm7Lgf/Lmna^+	involves: 129P2/OlaHsd * C57BL/6	MGI:4840105
ht10	Lmna^tm3Lgf/Lmna^+	involves: 129P2/OlaHsd * C57BL/6	MGI:3817507
ht11	Lmna^tm1.1Otin/Lmna^+	involves: 129P2/OlaHsd * C57BL/6NTac	MGI:7311569
ht12	Lmna^tm1Stw/Lmna^+	involves: 129S1/Sv	MGI:3620915
ht13	Lmna^tm1Stw/Lmna^+	involves: 129S1/Sv * C57BL/6J	MGI:3620917
ht14	Lmna^tm1Gbon/Lmna^+	involves: 129S2/SvPas * C57BL/6	MGI:3527795
ht15	Lmna^Gt(S7-1F1)Sor/Lmna^+	involves: 129S4/SvJaeSor * C57BL/6	MGI:5691991
ht16	Lmna^tm1.1Bliu/Lmna^+	involves: C57BL/6 * FVB/N	MGI:6423601
cx17	Lmna^tm7Lgf/Lmna^+ Zmpste24^tm1Sgy/Zmpste24^tm1Sgy	involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6	MGI:4840110
cx18	Lmna^tm6Lgf/Lmna^+ Zmpste24^tm1Sgy/Zmpste24^tm1Sgy	involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6	MGI:4457613
cx19	Lmna^tm1.1Otin/Lmna^+ Nat10^tm1a(KOMP)Wtsi/Nat10^+	involves: 129P2/OlaHsd * C57BL/6NTac	MGI:7311574
cx20	Lmna^tm1Stw/Lmna^+ Zmpste24^tm1Sgy/Zmpste24^tm1Sgy	involves: 129S1/Sv * 129S4/SvJae * C57BL/6	MGI:3620911
cx21	Lmna^tm1Stw/Lmna^+ Mlip^tm1.1(cre)Dzw/Mlip^tm1.1(cre)Dzw	involves: 129S1/Sv * C57BL/6	MGI:5907352
cx22	Lmna^tm2Lgf/Lmna^+ Zmpste24^tm1Sgy/Zmpste24^tm1Sgy	involves: 129S4/SvJae * C57BL/6	MGI:3620908

Genotype
MGI:4459466

ht1

• Allelic Composition: Lmna^Dhe/Lmna⁺
• Genetic Background: B6(D2)-Lmna^Dhe/TyGrsrJ

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

Lmna^Dhe/Lmna⁺ mice (right) have a sparse and gray coat, small size and small pinnae

mortality/aging

premature aging ( J:160175 )

• coat turns gray around 12 weeks of age

• however, lifespan is similar to controls

hematopoietic system

abnormal peritoneal macrophage morphology ( J:188496 )

• nuclear lamina meshwork of peritoneal macrophages appears rugous, disintegrative, or even collapsed and nuclear volumes are large

• however, mice exhibit normal macrophage migration elicited by thioglycollate

immune system

increased susceptibility to otitis media ( J:188496 )

• 100% penetrance of otitis media as early as P12

• cells of acute inflammatory response begin to perfuse the middle ear cavity, to infiltrate the mesenchymal cells and to block the Eustachian tube at P12

• at 8 weeks of age, cells of chronic inflammatory response pervade the entire middle ear cavity

• acute inflammatory cells and plasma fluids infiltrate the middle ear cavity extensively at P30

• from 2-8 months, various chronic suppurative middle ear inflammation occurs, with or without cholesteatoma

• macrophage activation is observed

abnormal peritoneal macrophage morphology ( J:188496 )

• nuclear lamina meshwork of peritoneal macrophages appears rugous, disintegrative, or even collapsed and nuclear volumes are large

• however, mice exhibit normal macrophage migration elicited by thioglycollate

craniofacial

abnormal cranial suture morphology ( J:160175 )

• patent sutures, in all cranial vault and facial sutures including the premaxillary/maxillary sutures

abnormal coronal suture morphology ( J:160175 )

• at six weeks the parietal and interparietal bones do not overlap and the suture tissue is hypoplastic, forming a much looser, thinner connection of the plates

abnormal lambdoid suture morphology ( J:160175 )

• suture tissue is hypoplastic, forming a much looser, thinner connection of the

abnormal sagittal suture morphology ( J:160175 )

• at 1 week of age, there is a gap between the the edges of the parietal bones and these bones are connected by a much thinner band of connective tissue

abnormal frontonasal suture morphology ( J:160175 )

• suture tissue is hypoplastic, forming a much looser, thinner connection of the plates

abnormal cranium size ( J:160175 )

• shorter, wider skull

decreased cranium height ( J:160175 )

decreased cranium width ( J:160175 )

small cranium ( J:160175 )

• in keeping with the reduction in body size

abnormal neurocranium morphology ( J:160175 )

• bone growth deficiency

shallow orbits ( J:160175 )

short upper incisors ( J:160175 )

• maxillary incisor and the diastema (the maxillary arch) are both abnormally short in the mutant

malocclusion ( J:160175 )

mandible hypoplasia ( J:160175 )

• underdeveloped lower jaw, inferior brachygnathism

short maxilla ( J:160175 )

• superior brachygnathism

short snout ( J:160175 )

• decreased nose length

short ears ( J:160175 )

• short pinnae

hearing/vestibular/ear

abnormal ear morphology ( J:188496 )

• ear hyperemia

short ears ( J:160175 )

• short pinnae

abnormal auditory bulla morphology ( J:188496 )

• bullae are smaller

abnormal middle ear morphology ( J:188496 )

• middle ear is undeveloped at P6

• middle ear cholesteatoma is seen in some ears

• typical cholesterol crystals are encysted by the hyperproliferative mucous epithelium and necrotic keratinizing squamous epithelial debris

• local suppurative abscess form in some middle ear cavities

abnormal middle ear development ( J:188496 )

• middle ear is undeveloped at P6

• the tympanic membrane is undeveloped at P12

abnormal auditory tube morphology ( J:188496 )

• abnormal positioning of the Eustachian tube with a greater mean intersection angle

• the mean length of the bony part of the Eustachian tube is smaller and width is greater than in wild-type resulting in a dilated anamorphic Eustachian tube

• at P12, with middle ear cavitation still progressing, dysplasia with dilation of the Eustachian tube is seen

• at 8 weeks of age, the Eustachian tube is distorted with dilation and exhibits poorly aligned and shorted or obsolescent cilia

abnormal middle ear epithelium morphology ( J:188496 )

• by 10 weeks of age, the cilia of the middle ear pseudostratified ciliated columnar epithelium exhibits severe pathology indicative of otitis media progression

increased middle ear goblet cell number ( J:188496 )

• proliferative goblet cells in the middle ear

abnormal tympanic membrane morphology ( J:188496 )

• tympanic membrane adherence

• the tympanic membrane is undeveloped at P12

• tympanic membrane shows a shortened subuliform light cone

tympanic membrane retraction ( J:188496 )

• at 8 weeks of age, the tympanic membrane is thickened and retracts into the middle ear cavity

abnormal ear physiology ( J:188496 )

• tympanometry shows that tympanometric values of volume are lower at 3 weeks of age but not other ages, values of compliance are lower at all time points from 3 weeks to 8 months of age, pressure of the middle ear is more negative, mean gradient values are higher at 1 month of age and 5 month old mice show an abnormal C type curve instead of the normal A type curve in scanning tympanograms

increased or absent threshold for auditory brainstem response ( J:188496 )

• ABR threshold from P16 to 4 months of age are elevated

abnormal distortion product otoacoustic emission ( J:188496 )

• at 3 months of age, mice have distortion product otoacoustin emission (DPOAE) 10-43.5 dB lower than those of wild-type mice

impaired hearing ( J:188496 )

• hearing impairment begins at lower stimulus frequencies (click and 8 kHz) and higher stimulus frequencies become affected with age

increased susceptibility to otitis media ( J:188496 )

• 100% penetrance of otitis media as early as P12

• cells of acute inflammatory response begin to perfuse the middle ear cavity, to infiltrate the mesenchymal cells and to block the Eustachian tube at P12

• at 8 weeks of age, cells of chronic inflammatory response pervade the entire middle ear cavity

• acute inflammatory cells and plasma fluids infiltrate the middle ear cavity extensively at P30

• from 2-8 months, various chronic suppurative middle ear inflammation occurs, with or without cholesteatoma

• macrophage activation is observed

respiratory system

abnormal nasopharynx morphology ( J:188496 )

• roof of the nasopharynx is abnormal as there is barely a gap between the tissue of the nasopharynx and the palate and the roof the nasopharynx is nearly fused to the palate bone

skeleton

abnormal cranial suture morphology ( J:160175 )

• patent sutures, in all cranial vault and facial sutures including the premaxillary/maxillary sutures

abnormal coronal suture morphology ( J:160175 )

• at six weeks the parietal and interparietal bones do not overlap and the suture tissue is hypoplastic, forming a much looser, thinner connection of the plates

abnormal lambdoid suture morphology ( J:160175 )

• suture tissue is hypoplastic, forming a much looser, thinner connection of the

abnormal sagittal suture morphology ( J:160175 )

• at 1 week of age, there is a gap between the the edges of the parietal bones and these bones are connected by a much thinner band of connective tissue

abnormal frontonasal suture morphology ( J:160175 )

• suture tissue is hypoplastic, forming a much looser, thinner connection of the plates

abnormal cranium size ( J:160175 )

• shorter, wider skull

decreased cranium height ( J:160175 )

decreased cranium width ( J:160175 )

small cranium ( J:160175 )

• in keeping with the reduction in body size

abnormal neurocranium morphology ( J:160175 )

• bone growth deficiency

shallow orbits ( J:160175 )

short upper incisors ( J:160175 )

• maxillary incisor and the diastema (the maxillary arch) are both abnormally short in the mutant

malocclusion ( J:160175 )

mandible hypoplasia ( J:160175 )

• underdeveloped lower jaw, inferior brachygnathism

short maxilla ( J:160175 )

• superior brachygnathism

decreased bone mineral content ( J:160175 )

• of skull

decreased bone mineral density ( J:160175 )

• low bone mineral density of skull and whole body

abnormal bone mineralization ( J:160175 )

• skull mineralization defects

adipose tissue

decreased total body fat amount ( J:160175 )

• in males

pigmentation

abnormal coat/hair pigmentation ( J:160175 )

• turns gray around 12 weeks of age

cellular

abnormal cell nucleus size ( J:171665 )

• nuclei appear larger and nuclear volume is greater than in wild-type mice

aneuploidy ( J:171665 )

• fibroblasts exhibit extensive aneuploidy, with a higher fraction of cells greater than 4C and chromosome numbers ranging from 38 to 104 chromosomes per nucleus

abnormal nuclear lamina morphology ( J:171665 , J:160175 , J:188496 )

• skin fibroblasts exhibit aberrant nuclear lamina morphology, with nuclear membranes showing large blebs and lobulations (J:171665)

• patches of irregularity in the normal criss-cross pattern of LMNA and LMNB meshworks are seen (J:171665)

• grossly abnormal nuclear lamina of cultured primary calvarial osteoblasts with various numbers of nuclear lamina blebs, discreet balloon-like outpocketings of the nuclear envelope (J:160175)

• nuclear lamina meshwork of peritoneal macrophages appears rugous, disintegrative, or even collapsed (J:188496)

increased middle ear goblet cell number ( J:188496 )

• proliferative goblet cells in the middle ear

abnormal cell cycle ( J:171665 )

• mutant cell cultures have an increased proportion of cells in anaphase compared to normal cells

abnormal mitosis ( J:171665 )

• mitotic defects such as aneuploidy, lagging chromosomes, and anaphase bridges associated with low levels of activated RB1 and CAPD3

• LMNA expression and assembly at the nuclear lamina is perturbed during interphase and mitosis

• fibroblasts exhibit mitotic chromosome cohesion defects

abnormal mitotic spindle assembly checkpoint ( J:171665 )

• defects in mitotic spindle checkpoint

decreased fibroblast proliferation ( J:171665 )

• fibroblasts grow significantly slower that wild-type fibroblasts

abnormal DNA replication ( J:171665 )

• increase in DNA damage in interphase

growth/size/body

short upper incisors ( J:160175 )

• maxillary incisor and the diastema (the maxillary arch) are both abnormally short in the mutant

malocclusion ( J:160175 )

mandible hypoplasia ( J:160175 )

• underdeveloped lower jaw, inferior brachygnathism

short maxilla ( J:160175 )

• superior brachygnathism

short snout ( J:160175 )

• decreased nose length

short ears ( J:160175 )

• short pinnae

decreased body size ( J:160175 )

decreased body weight ( J:160175 )

reproductive system

reduced female fertility ( J:160175 )

♀

vision/eye

shallow orbits ( J:160175 )

exophthalmos ( J:160175 )

ocular hypotelorism ( J:160175 )

integument

abnormal coat/hair pigmentation ( J:160175 )

• turns gray around 12 weeks of age

sparse hair ( J:160175 )

rough coat ( J:160175 )

• scruffy coat

flaky skin ( J:160175 )

homeostasis/metabolism

abnormal DNA replication ( J:171665 )

• increase in DNA damage in interphase

increased circulating phosphate level ( J:188496 )

• females exhibit a lower calcium/phosphorus ratio due to an increase of phosphorus rather than a decrease in calcium

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
otitis media		DOID:10754		J:188496
progeria		DOID:3911	OMIM:176670	J:171665

Genotype
MGI:7518590

ht2

• Allelic Composition: Lmna^em1Fenz/Lmna⁺
• Genetic Background: C57BL/6-Lmna^em1Fenz

adipose tissue

adipose tissue phenotype ( J:338760 )

N • normal fat deposits when fed regular chow (RCD)

increased brown adipose tissue mass ( J:338760 )

♂ • after 10 weeks on high-fat diet (HFD)

abnormal inguinal fat pad morphology ( J:338760 )

♂ • smaller and more disorganized adipocytes and increased inflammation and senescence after 10 weeks on high-fat diet (HFD)

increased renal fat pad weight ( J:338760 )

♂ • after 10 weeks on high-fat diet (HFD)

increased abdominal fat pad weight ( J:338760 )

♂ • after 10 weeks on high-fat diet (HFD)

decreased white adipose tissue mass ( J:338760 )

♂ • lower epididymal white adipose tissue (eWAT) mass and smaller adipocytes after 10 weeks on high-fat diet (HFD)

♂ • normal inguinal white adipose tissue (iWAT) mass after 10 weeks on high-fat diet (HFD)

cellular

abnormal respiratory electron transport chain ( J:338760 )

♂ • impaired in liver and inguinal white adipose tissue (iWAT) mitochondria after 23 weeks on high-fat diet (HFD)

growth/size/body

increased body weight ( J:338760 )

♂ • after 10 weeks on high-fat diet (HFD)

♂ • normal food intake when on high-fat diet (HFD)

♂ • normal body weight when fed regular chow (RCD)

homeostasis/metabolism

increased circulating cholesterol level ( J:338760 )

♂ • after 23 weeks on high-fat diet (HFD)

increased circulating LDL cholesterol level ( J:338760 )

♂ • after 23 weeks on high-fat diet (HFD)

increased circulating alanine transaminase level ( J:338760 )

♂ • after 23 weeks on high-fat diet (HFD)

increased circulating alkaline phosphatase level ( J:338760 )

♂ • after 23 weeks on high-fat diet (HFD)

increased circulating aspartate transaminase level ( J:338760 )

♂ • after 23 weeks on high-fat diet (HFD)

impaired glucose tolerance ( J:338760 )

♂ • after 23 weeks on high-fat diet (HFD)

♂ • normal when fed regular chow (RCD)

insulin resistance ( J:338760 )

♂ • after 23 weeks on high-fat diet (HFD)

♂ • normal when fed regular chow (RCD)

increased liver triglyceride level ( J:338760 )

♂ • after 23 weeks on high-fat diet (HFD)

liver/biliary system

increased liver triglyceride level ( J:338760 )

♂ • after 23 weeks on high-fat diet (HFD)

hepatic steatosis ( J:338760 )

♂ • after 10 weeks on high-fat diet (HFD)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progeria		DOID:3911	OMIM:176670	J:338760

Genotype
MGI:5757315

ht3

• Allelic Composition: Lmna^{tm1b(EUCOMM)Wtsi}/Lmna⁺
• Genetic Background: C57BL/6N-Lmna^{tm1b(EUCOMM)Wtsi}/Ics
• Cell Lines: EPD0419_6_A02

Data Sources

IMPC Data for Lmna

homeostasis/metabolism

improved glucose tolerance ( J:211773 )

♂

IMPC - ICS

limbs/digits/tail

short tibia ( J:211773 )

IMPC - ICS

nervous system

abnormal optic disk morphology ( J:211773 )

IMPC - ICS

skeleton

short tibia ( J:211773 )

IMPC - ICS

vision/eye

abnormal optic disk morphology ( J:211773 )

IMPC - ICS

abnormal cornea morphology ( J:211773 )

IMPC - ICS

cornea ulcer ( J:211773 )

IMPC - ICS

Genotype
MGI:5906504

ht4

• Allelic Composition: Lmna^tm2.1Gbon/Lmna⁺
• Genetic Background: involves: 129 * C57BL/6

mortality/aging

premature death ( J:198526 )

• mice die between 35 and 70 weeks of age

• death occurs about 15-20 weeks after reduced fractional shortening

cardiovascular system

cardiac muscle degeneration ( J:198526 )

• at end stage, degenerative changes are seen in cardiac tissues with disrupted sarcomeres, myofibrillar lysis, vesicular proliferation of sarcomeric reticulum, intracytoplasmic junctions, electron dense residual bodies, and pericellular fibrosis

abnormal heart morphology ( J:198526 )

• large proportion of nuclei in the heart are more elongated and thinner at 10, 30, and 57 weeks of age and these nuclei have enlarged nuclear intermembrane space in young asymptomatic mice

• mice with mild cardiac dysfunction show severe alterations in cardiac nuclei, such as extremely enlarged nuclear intermembrane space, accumulation of large perinuclear vacuoles, or envelope rupture with extravasations of chromatin into the cytoplasm

increased heart atrium size ( J:198526 )

• atrial enlargement

cardiac hypertrophy ( J:198526 )

dilated heart left ventricle ( J:198526 )

• increase in left ventricular end-diastolic diameter

• however, no major wall thinning is seen

cardiac fibrosis ( J:198526 )

• at end stage, the left ventricle shows slight fibrosis

dilated cardiomyopathy ( J:198526 )

• mice exhibit decreased fractional shortening and increased left ventricle end-diastolic diameter indicating dilated cardiomyopathy

decreased cardiac muscle contractility ( J:198526 )

• progressive development of cardiac dysfunction from 32 to 70 weeks of age

• decrease in fractional shortening which starts a bit earlier in males than in females

abnormal heart echocardiography feature ( J:198526 )

• echocardiography indicates decreased fractional shortening and increased left ventricle end-diastolic diameter without wall thinning

decreased heart rate ( J:198526 )

• slight bradycardia is seen at the very end stages of the dilated cardiomyopathy

prolonged PR interval ( J:198526 )

• higher PR interval is seen at the very end stages of the dilated cardiomyopathy

prolonged QRS complex duration ( J:198526 )

• QRS complex broadening is seen at the very end stages of the dilated cardiomyopathy

congestive heart failure ( J:198526 )

• mice eventually present with congestive heart failure demonstrated by left ventricle hypokinesia and lung edema

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:198526 )

N • 57 week old mice do not exhibit metabolic defects

pulmonary edema ( J:198526 )

• lung edema in mice with congestive heart failure

muscle

muscle phenotype ( J:198526 )

N • 57 week old mice do not exhibit skeletal muscle defects or skeletal muscle contractile function defects

cardiac muscle degeneration ( J:198526 )

• at end stage, degenerative changes are seen in cardiac tissues with disrupted sarcomeres, myofibrillar lysis, vesicular proliferation of sarcomeric reticulum, intracytoplasmic junctions, electron dense residual bodies, and pericellular fibrosis

dilated cardiomyopathy ( J:198526 )

• mice exhibit decreased fractional shortening and increased left ventricle end-diastolic diameter indicating dilated cardiomyopathy

decreased cardiac muscle contractility ( J:198526 )

• progressive development of cardiac dysfunction from 32 to 70 weeks of age

• decrease in fractional shortening which starts a bit earlier in males than in females

abnormal sarcomere morphology ( J:198526 )

• cardiac sarcomeres are disrupted at end stage of disease and vesicular proliferation of sarcomeric reticulum is seen

respiratory system

pulmonary edema ( J:198526 )

• lung edema in mice with congestive heart failure

growth/size/body

cardiac hypertrophy ( J:198526 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
dilated cardiomyopathy 1A		DOID:0110425	OMIM:115200	J:198526

Genotype
MGI:3837138

ht5

• Allelic Composition: Lmna^tm4Lgf/Lmna⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

Rib fractures in Lmna^tm4Lgf/Lmna⁺ and Lmna^tm1Lgf/Lmna⁺ mice

mortality/aging

premature death ( J:146099 )

• mice die between 35 and 45 weeks

cellular

abnormal cell nucleus morphology ( J:146099 )

• mouse embryonic fibroblasts exhibit misshapen nuclei unlike wild-type cells

growth/size/body

decreased body weight ( J:146099 )

skeleton

rib fractures ( J:146099 )

• mice exhibit more rib fractures than in wild-type mice but less than in Lmna^tm1Lgf heterozygotes

Genotype
MGI:5295754

ht6

• 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:3817506

ht7

• Allelic Composition: Lmna^tm1Lgf/Lmna⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

Lmna^tm1Lgf/Lmna⁺ mice exhibt kyphosis, rib fractures, and skull abnormalities

mortality/aging

premature death ( J:113119 , J:141165 , J:146099 )

• 50% of mice become malnourished and are euthanized by week 27 (J:113119)

• all mice die by 40 week of age (J:113119)

• mice die by 35 weeks of age (J:141165)

• mice die at 30 weeks (J:146099)

skeleton

abnormal cranial suture morphology ( J:113119 )

• cranial sutures have a zigzag appearance

abnormal zygomatic arch morphology ( J:113119 )

• by week 18, mice develop osteolytic lesions in the posterior portion of the zygomatic arch

micrognathia ( J:113119 )

abnormal rib morphology ( J:113119 , J:141165 )

• mice develop osteolytic lesions in the ribs (J:113119)

• ribs exhibit decreased bone density and cortical thickness compared to wild-type mice (J:141165)

rib fractures ( J:113119 , J:141165 )

• mice are pre-disposed to rib fractures near the costovertebral junction unlike wild-type mice (J:113119)

• however, treatment with FTI (a farnesyltransferase inhibitor) improves phenotype (J:113119)

• mice develop progressive rib fractures near the costovertebral joints as they age (J:141165)

kyphosis ( J:113119 , J:141165 )

• mice develop kyphosis (J:113119)

• however, treatment with FTI (a farnesyltransferase inhibitor) improves phenotype (J:113119)

abnormal bone structure ( J:113119 )

• mice exhibit osteolytic lesions on the ribs, zygomatic arch, clavicle, scapula, calvarium and mandible

decreased bone mineral density ( J:141165 )

• ribs exhibit decreased bone density compared to wild-type mice

abnormal bone mineralization ( J:113119 )

• mice exhibit poor bone mineralization

• however, treatment with FTI (a farnesyltransferase inhibitor) improves phenotype

adipose tissue

decreased subcutaneous adipose tissue amount ( J:113119 )

• mice exhibit reduced subcutaneous adipose tissue compared to wild-type mice

• however, treatment with FTI (a farnesyltransferase inhibitor) improves phenotype

decreased abdominal adipose tissue amount ( J:113119 )

• mice exhibit decreased abdominal adipose tissue compared to wild-type mice

• however, treatment with FTI (a farnesyltransferase inhibitor) improves phenotype

decreased percent body fat/body weight ( J:141165 )

cellular

abnormal cell nucleus morphology ( J:100220 , J:141165 , J:146099 )

• primary fibroblast lines that are heterozygous display increased nuclear blebbing, which is diminished by treatment with farnesyltransferase blocker PB-43 (J:100220)

• mouse embryonic fibroblasts exhibit misshapen nuclei (J:141165)

• mouse embryonic fibroblasts exhibit misshapen nuclei unlike wild-type cells (J:146099)

growth/size/body

micrognathia ( J:113119 )

decreased body weight ( J:141165 , J:146099 )

weight loss ( J:113119 )

• mice begin to lose weight at 6 to 8 weeks of age

• however, treatment with FTI (a farnesyltransferase inhibitor) improves phenotype

behavior/neurological

behavior/neurological phenotype ( J:113119 )

N • unlike Zmpste24 knockout mice, grip strength is normal

craniofacial

abnormal cranial suture morphology ( J:113119 )

• cranial sutures have a zigzag appearance

abnormal zygomatic arch morphology ( J:113119 )

• by week 18, mice develop osteolytic lesions in the posterior portion of the zygomatic arch

micrognathia ( J:113119 )

integument

decreased subcutaneous adipose tissue amount ( J:113119 )

• mice exhibit reduced subcutaneous adipose tissue compared to wild-type mice

• however, treatment with FTI (a farnesyltransferase inhibitor) improves phenotype

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progeria		DOID:3911	OMIM:176670	J:113119

Genotype
MGI:5754489

ht8

• Allelic Composition: Lmna^tm11Lgf/Lmna⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

mortality/aging

premature death ( J:220988 )

• mice show sporadic death beginning at 3-4 months of age, with 50% dying by 5.5 months of age and some surviving to 11-12 months

growth/size/body

weight loss ( J:220988 )

• majority of mice lose about 20% of their body weight by 5-6 months of age

digestive/alimentary system

abnormal interstitial cell of Cajal morphology ( J:220988 )

• marker analysis indicates a decrease in the interstitial cells of Cajal in the gastrointestinal tract

abnormal esophageal squamous epithelium morphology ( J:220988 )

• esophagus shows a cornified squamous epithelium

abnormal esophageal smooth muscle morphology ( J:220988 )

• esophagus appears yellow, reflecting reduced amounts of muscle within the muscularis externa

• esophagus shows thinning of the inner circular and outer longitudinal layers of the muscularis external, pathology similar to achalasia

dilated esophagus ( J:220988 )

• by 4 months of age, all mice show a dilated esophagus that often contains food

distended cecum ( J:220988 )

abnormal colon morphology ( J:220988 )

• dilated proximal colon

esophageal achalasia ( J:220988 )

• esophagus shows thinning of the inner circular and outer longitudinal layers of the muscularis external, pathology similar to achalasia

muscle

abnormal esophageal smooth muscle morphology ( J:220988 )

• esophagus appears yellow, reflecting reduced amounts of muscle within the muscularis externa

• esophagus shows thinning of the inner circular and outer longitudinal layers of the muscularis external, pathology similar to achalasia

esophageal achalasia ( J:220988 )

• esophagus shows thinning of the inner circular and outer longitudinal layers of the muscularis external, pathology similar to achalasia

nervous system

nervous system phenotype ( J:220988 )

N • cerebral cortex appears normal and mice show no obvious pathology in the brain at 5 months of age

abnormal enteric neuron morphology ( J:220988 )

• maker analysis shows few enteric neurons and nerve fibers in the esophagus or in the gastrointestinal tract

abnormal cholinergic neuron morphology ( J:220988 )

• marker analysis indicates a decrease in the level of cholinergic neurons in the esophagus

skeleton

skeleton phenotype ( J:220988 )

N • mice do not exhibit osteolytic lesions or rib fractures

cellular

abnormal interstitial cell of Cajal morphology ( J:220988 )

• marker analysis indicates a decrease in the interstitial cells of Cajal in the gastrointestinal tract

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
achalasia		DOID:9164	OMIM:200400	J:220988

Genotype
MGI:4840105

ht9

• Allelic Composition: Lmna^tm7Lgf/Lmna⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

cellular

abnormal cell nucleus morphology ( J:165928 )

• misshapen

Genotype
MGI:3817507

ht10

• Allelic Composition: Lmna^tm3Lgf/Lmna⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

mortality/aging

premature death ( J:141165 )

• mice die by 50 weeks of age

skeleton

skeleton phenotype ( J:141165 )

N • mice exhibit normal bone density and cortical thickness in the ribs

rib fractures ( J:141165 )

• mice develop progressive rib fractures near the costovertebral joints as they age that are not as numerous as in Lmna^tm1Lgf heterozygotes at the time of death

kyphosis ( J:141165 )

• mice develop kyphosis that is not as severe as in Lmna^tm1Lgf heterozygotes

adipose tissue

decreased percent body fat/body weight ( J:141165 )

• mice exhibit reduced body fat compared to in wild-type mice but not as severely as in Lmna^tm1Lgf heterozygotes

growth/size/body

decreased body weight ( J:141165 )

• mice exhibit reduced body weight compared to wild-type mice that is not as severe as in Lmna^tm1Lgf heterozygotes

Genotype
MGI:7311569

ht11

• 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:3620915

ht12

• Allelic Composition: Lmna^tm1Stw/Lmna⁺
• Genetic Background: involves: 129S1/Sv

cellular

abnormal cell nucleus morphology ( J:58702 )

• in many MEFs, nuclei appear elongated but distribution of nuclear envelope proteins is normal except for increased levels of cytoplasmic emerin

Genotype
MGI:3620917

ht13

• Allelic Composition: Lmna^tm1Stw/Lmna⁺
• Genetic Background: involves: 129S1/Sv * C57BL/6J

homeostasis/metabolism

increased circulating insulin level ( J:75101 )

• on a high fat diet, females develop mild insulin resistance that correlates with increased body weight, no insulin resistance is seen in males

• on a normal diet, serum glucose, insulin, and triglyceride levels are normal, insulin sensitivity and glucose tolerance

insulin resistance ( J:75101 )

• on a high fat diet, females develop increased insulin but not glucose levels

adipose tissue

adipose tissue phenotype ( J:75101 )

N • no signs of lipoatrophy are seen

liver/biliary system

liver/biliary system phenotype ( J:75101 )

N • liver morphology is normal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
NOT	familial partial lipodystrophy	DOID:0050440	OMIM:PS151660	J:75101

Genotype
MGI:3527795

ht14

• Allelic Composition: Lmna^tm1Gbon/Lmna⁺
• Genetic Background: involves: 129S2/SvPas * C57BL/6

normal phenotype

no abnormal phenotype detected ( J:95528 )

• indistinguishable from wild-type with regard to phenotype and life expectancy

Genotype
MGI:5691991

ht15

• Allelic Composition: Lmna^{Gt(S7-1F1)Sor}/Lmna⁺
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6

normal phenotype

no abnormal phenotype detected ( J:221850 )

• heterozygotes are indistinguishable from wild-type mice in all assays tested and do not develop progressive electrophysiological abnormalities or cardiac left ventricle dilation up to one year of age

Genotype
MGI:6423601

ht16

• Allelic Composition: Lmna^tm1.1Bliu/Lmna⁺
• Genetic Background: involves: C57BL/6 * FVB/N

mortality/aging

premature death ( J:287256 )

• shortened life span

growth/size/body

postnatal growth retardation ( J:287256 )

cardiovascular system

abnormal vasodilation ( J:287256 )

• acetylcholine-induced thoracic aorta relaxation is compromised

muscle

abnormal vasodilation ( J:287256 )

• acetylcholine-induced thoracic aorta relaxation is compromised

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progeria		DOID:3911	OMIM:176670	J:287256

Genotype
MGI:4840110

cx17

• Allelic Composition: Lmna^tm7Lgf/Lmna⁺; Zmpste24^tm1Sgy/Zmpste24^tm1Sgy
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6

mortality/aging

mortality/aging ( J:165928 )

N • mice exhibit normal survival

skeleton

decreased susceptibility to bone fracture ( J:165928 )

• compared to in Zmpste24^tm1Sgy homozygotes

growth/size/body

growth/size/body region phenotype ( J:165928 )

N • body weight is normal

Genotype
MGI:4457613

cx18

• Allelic Composition: Lmna^tm6Lgf/Lmna⁺; Zmpste24^tm1Sgy/Zmpste24^tm1Sgy
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6

mortality/aging

decreased survivor rate ( J:160705 )

• survival is worse than in Zmpste24 single mutants

premature death ( J:160705 )

• survival is worse than in Zmpste24 single mutants

growth/size/body

decreased body weight ( J:160705 )

• smaller than Zmpste24 single mutants

Genotype
MGI:7311574

cx19

• 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

Genotype
MGI:3620911

cx20

• Allelic Composition: Lmna^tm1Stw/Lmna⁺; Zmpste24^tm1Sgy/Zmpste24^tm1Sgy
• Genetic Background: involves: 129S1/Sv * 129S4/SvJae * C57BL/6

skeleton

skeleton phenotype ( J:95274 )

N • no bone fractures or other skeletal abnormalities are seen

cellular

cellular phenotype ( J:95274 )

N • normal nuclear envelope morphology in MEFs

growth/size/body

growth/size/body region phenotype ( J:95274 )

N • improved growth compared to mice homozygous for Zmpste24^tm1Sgy only

muscle

muscle phenotype ( J:95274 )

N • muscle strength is similar to wild-type

Genotype
MGI:5907352

cx21

• Allelic Composition: Lmna^tm1Stw/Lmna⁺; Mlip^{tm1.1(cre)Dzw}/Mlip^{tm1.1(cre)Dzw}
• Genetic Background: involves: 129S1/Sv * C57BL/6

cardiovascular system

dilated heart left ventricle ( J:227485 )

• progressive increase in left ventricular internal dimension at end-diastole from 6 to 12 months of age

dilated cardiomyopathy ( J:227485 )

• at 12 months of age

decreased cardiac muscle contractility ( J:227485 )

• progressive decrease in fractional shortening from 6 to 12 months of age

muscle

dilated cardiomyopathy ( J:227485 )

• at 12 months of age

decreased cardiac muscle contractility ( J:227485 )

• progressive decrease in fractional shortening from 6 to 12 months of age

Genotype
MGI:3620908

cx22

• Allelic Composition: Lmna^tm2Lgf/Lmna⁺; Zmpste24^tm1Sgy/Zmpste24^tm1Sgy
• Genetic Background: involves: 129S4/SvJae * C57BL/6

skeleton

skeleton phenotype ( J:106473 )

N • no bone fractures or other skeletal abnormalities are seen

cellular

cellular phenotype ( J:106473 )

N • far fewer misshapen nuclei in MEFs

growth/size/body

growth/size/body region phenotype ( J:106473 )

N • normal growth

muscle

muscle phenotype ( J:106473 )

N • muscle strength is similar to wild-type