Phenotypes associated with this allele

• Allele Symbol: Ctsl^tm1Cptr
• Allele Name: targeted mutation 1, Christoph Peters
• Allele ID: MGI:2136432
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Ctsl^tm1Cptr/Ctsl^tm1Cptr	involves: 129P2/OlaHsd	MGI:5810302
hm2	Ctsl^tm1Cptr/Ctsl^tm1Cptr	involves: 129P2/OlaHsd * C57BL/6J	MGI:2175824
hm3	Ctsl^tm1Cptr/Ctsl^tm1Cptr	NOD.129P2-Ctsl^tm1Cptr	MGI:4420985
ht4	Ctsl^tm1Cptr/Ctsl^+	NOD.129P2-Ctsl^tm1Cptr	MGI:4420986
cx5	Ctsk^tm1Psa/Ctsk^tm1Psa Ctsl^tm1Cptr/Ctsl^tm1Cptr	involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6J	MGI:3695741
cx6	Ctsb^tm1Jde/Ctsb^tm1Jde Ctsl^tm1Cptr/Ctsl^tm1Cptr	involves: 129P2/OlaHsd * C57BL/6J	MGI:3628482

Genotype
MGI:5810302

hm1

• Allelic Composition: Ctsl^tm1Cptr/Ctsl^tm1Cptr
• Genetic Background: involves: 129P2/OlaHsd

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

Ctsl^tm1Cptr/Ctsl^tm1Cptr embryos show severe accumulation of vesicles in the yolk sac endoderm

cardiovascular system

abnormal myocardium layer morphology ( J:76333 )

• increase of connective tissue in the myocardium in 1 year old mice

• most cells in the myocardium of 1 year old mice contain multiple, large, and fused lysosomes containing heterogeneous electron-dense material

abnormal myocardial fiber morphology ( J:76333 )

• cardiomyocytes exhibit about twice as many nuclei per mm³ than controls, resulting in a decrease in volume of cytoplasm per nucleus

• many nuclei of cardiomyocytes are pleomorphic

increased heart left atrium size ( J:76333 )

enlarged heart ( J:76333 )

• by 12 months of age, about 75% of hearts show slight to moderate enlargement, with 25% showing severe enlargement

heart left ventricle hypertrophy ( J:76333 )

• moderate left ventricular hypertrophy, with an increase of left ventricular dimensions in 1 year old mice

• 4 of 14 mice exhibit a severe enlargement of the left ventricle at the end of systole and diastole, accompanied by a 1.5-fold higher mass of the left ventricle

increased heart weight ( J:76333 )

• from 6 months of age, the relative heart weights increase

cardiac interstitial fibrosis ( J:76333 )

• patches of interstitial fibrosis in hearts are first seen at 4 months of age

• however, inflammatory cell infiltrates are not seen in hearts

abnormal cardiovascular system physiology ( J:76333 )

• the cardiac index, describing the amount of heart work needed to maintain sufficient blood perfusion of the body, is increased in mice with severe ventricular and atrial dilation

• the maximal and average pressure gradients at the aortic valve of mice with extremely dilated hearts are elevated 3- to 4-fold

dilated cardiomyopathy ( J:76333 )

decreased cardiac muscle contractility ( J:76333 )

• reduction in contraction of interventricular septum and posteriolateral wall

decreased heart left ventricle muscle contractility ( J:76333 )

• fractional shortening is reduced in all mice (left ventricular contraction), without further contraction reduction in mice with extreme ventricular enlargement

• the diameter and volume of the left ventricle at maximal contraction (the end of systole) is enhanced in all mice

abnormal heart echocardiography feature ( J:76333 )

• all mice show increased left ventricular end-systolic diameter while mice with severely enlarged hearts exhibit increased left ventricular end-systolic diameter, end-diastolic volume, left ventricular end-diastolic diameter, left ventricle mass, left atrium diameter, maximum velocity of flow in the pw-doppler over aortic valve, maximum aortic pressure gradient, average aortic pressure gradient, and cardiac index

mitral valve regurgitation ( J:76333 )

• 4 of 14 mice show regurgitation at the mitral and aortic valves indicates valve insufficiencies in dilated hearts

aortic valve regurgitation ( J:76333 )

• 4 of 14 mice show regurgitation at the mitral and aortic valves indicates valve insufficiencies in dilated hearts

abnormal heartbeat ( J:76333 )

• one mouse exhibits monomorphic ventricular extrabeats

increased heart rate ( J:76333 )

• 3 of 14 mice exhibit supraventricular tachycardia

atrioventricular block ( J:76333 )

• one mouse exhibits atrioventricular block

abnormal heart electrocardiography waveform feature ( J:76333 )

• the interval between the R- and T-waves of the ECG that reports activation and repolarization time of the ventricle is prolonged, with a flat and wide T-wave morphology

abnormal R wave ( J:76333 )

• mice show higher R-wave voltages in standard limb lead II as an electrocardiographic sign of left ventricular hypertrophy

abnormal T wave ( J:76333 )

• flat and wide T-wave morphology

embryo

abnormal visceral yolk sac morphology ( J:216506 )

• at E8.0, the extraembryonic yolk sac is more opaque and displays wrinkles and an uneven bulged surface, unlike the translucent control yolk sac tissue which shows a relatively smooth surface

abnormal visceral endoderm morphology ( J:216506 )

• at E8.0, the extraembryonic visceral endoderm shows wrinkled morphology, thickening of the visceral endoderm cell layer, and increased number and size of vesicular structures

• visceral endoderm cells are significantly enlarged and filled with large vesicular structures staining positive for glycoproteins in periodic acid-Schiff staining as well as for the lysosomal marker LAMP-1, indicating that accumulating vesicles are lysosomes

• however, early development of the epiblast appears normal

integument

increased keratinocyte proliferation ( J:216506 )

• mice exhibit increased keratinocyte proliferation in the basal layer of back skin epidermis, as shown by Ki67 staining

alopecia ( J:216506 )

• mice exhibit periodical hair loss

epidermal hyperplasia ( J:216506 )

• mice exhibit epidermal hyperplasia with numerous proliferating cells

thick epidermis ( J:216506 )

mortality/aging

postnatal lethality, incomplete penetrance ( J:76333 )

• pups have a mortality rate of 15% compared to 6% for wild-type mice

• however, mortality rate of adults is not increased in mice up to 12 months of age

muscle

abnormal myocardium layer morphology ( J:76333 )

• increase of connective tissue in the myocardium in 1 year old mice

• most cells in the myocardium of 1 year old mice contain multiple, large, and fused lysosomes containing heterogeneous electron-dense material

abnormal myocardial fiber morphology ( J:76333 )

• cardiomyocytes exhibit about twice as many nuclei per mm³ than controls, resulting in a decrease in volume of cytoplasm per nucleus

• many nuclei of cardiomyocytes are pleomorphic

heart left ventricle hypertrophy ( J:76333 )

• moderate left ventricular hypertrophy, with an increase of left ventricular dimensions in 1 year old mice

• 4 of 14 mice exhibit a severe enlargement of the left ventricle at the end of systole and diastole, accompanied by a 1.5-fold higher mass of the left ventricle

dilated cardiomyopathy ( J:76333 )

decreased cardiac muscle contractility ( J:76333 )

• reduction in contraction of interventricular septum and posteriolateral wall

decreased heart left ventricle muscle contractility ( J:76333 )

• fractional shortening is reduced in all mice (left ventricular contraction), without further contraction reduction in mice with extreme ventricular enlargement

• the diameter and volume of the left ventricle at maximal contraction (the end of systole) is enhanced in all mice

immune system

decreased CD4-positive, alpha-beta T cell number ( J:216506 )

• at 8 weeks of age, mice exhibit a significantly decreased CD4+ T cell number in spleen relative to wild-type controls (4.2% versus 15.4%, respectively)

cellular

cardiac interstitial fibrosis ( J:76333 )

• patches of interstitial fibrosis in hearts are first seen at 4 months of age

• however, inflammatory cell infiltrates are not seen in hearts

abnormal lysosome morphology ( J:216506 )

• at E8.0, embryos show a severe lysosomal storage phenotype in the visceral endoderm of the extraembryonic yolk sac

increased keratinocyte proliferation ( J:216506 )

• mice exhibit increased keratinocyte proliferation in the basal layer of back skin epidermis, as shown by Ki67 staining

hematopoietic system

decreased CD4-positive, alpha-beta T cell number ( J:216506 )

• at 8 weeks of age, mice exhibit a significantly decreased CD4+ T cell number in spleen relative to wild-type controls (4.2% versus 15.4%, respectively)

growth/size/body

enlarged heart ( J:76333 )

• by 12 months of age, about 75% of hearts show slight to moderate enlargement, with 25% showing severe enlargement

heart left ventricle hypertrophy ( J:76333 )

• moderate left ventricular hypertrophy, with an increase of left ventricular dimensions in 1 year old mice

• 4 of 14 mice exhibit a severe enlargement of the left ventricle at the end of systole and diastole, accompanied by a 1.5-fold higher mass of the left ventricle

increased heart weight ( J:76333 )

• from 6 months of age, the relative heart weights increase

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
dilated cardiomyopathy		DOID:12930	OMIM:PS115200	J:76333

Genotype
MGI:2175824

hm2

• Allelic Composition: Ctsl^tm1Cptr/Ctsl^tm1Cptr
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J

mortality/aging

postnatal lethality, incomplete penetrance ( J:70118 )

• up to weaning, homozygotes exhibit increased postnatal mortality relative to wild-type mice (15% vs 6%, respectively)

• thereafter, a normal mortality rate is observed for an interval of greater than 50 weeks

endocrine/exocrine glands

abnormal thyroid gland morphology ( J:83877 )

• cells with enlarged lysosomes

homeostasis/metabolism

amyloidosis ( J:116135 )

• significantly smaller amounts of amyloid deposited in the spleen

• amyloid deposits of full sized protein

abnormal thyroid hormone level ( J:83877 )

• 5-6 fold increases in thyroglobulin levels

decreased thyroxine level ( J:83877 )

• significantly reduced levels of T4

hematopoietic system

increased regulatory T cell number ( J:153355 )

• mice exhibit an increase in Foxp3-expressing T cells

immune system

increased regulatory T cell number ( J:153355 )

• mice exhibit an increase in Foxp3-expressing T cells

integument

increased keratinocyte proliferation ( J:70118 )

• homozygotes display hyperproliferation of basal epidermal keratinocytes while the number of apoptotic cells in the epidermis remains unaffected

alopecia ( J:70118 )

• homozygotes start to lose their fur at P21, beginning at the head and progressing toward the tail region of the back, until they are almost nude at P28-P30

• a new coat starts to grow during the onset of the anagen phase, followed by a new wave of spatially restricted hair loss at 7 weeks

• mature homozygotes are always partially devoid of hair

delayed hair appearance ( J:70118 )

• appearance of the first pelage fur is delayed by 2 days

abnormal hair shaft morphology ( J:70118 )

• at P6, mutant hair shafts are significantly shorter and not yet emerging through the skin; however, hair follicle density is normal

abnormal hair follicle development ( J:70118 )

• at P6, homozygous neonates exhibit delayed hair follicle morphogenesis

underdeveloped hair follicles ( J:70118 )

• at P6, wild-type mice display 51.4% stage 7 and 48.6% stage 8 hair follicles, whereas homozygotes exhibit 84.4% of hair follicles in stage 7 of hair follicle morphogenesis

hair follicle outer root sheath hyperplasia ( J:70118 )

• at ~P20 (during hair follicle regression), the outer root sheath displays significant hyperplasia

dilated piliary canal ( J:70118 )

• at P20, mutant hair follicles display a pathological disintegration of the developing club hair; as a result, the hair canal is distended

absent vibrissae ( J:70118 )

• no vibrissae are identified at birth

abnormal hair cycle ( J:70118 )

• homozygotes exhibit a significant delay in catagen progression as well as premature entry into anagen

• at P20, 95% of wild-type hair follicles are in catagen stages VII or VIII, whereas mutant hair follicles are predominantly in catagen VI (35.2%) and VII (46.3%)

• at P28, 69% of wild-type hair follicles are in telogen, whereas all mutant hair follicles have already prematurely entered anagen (anagen V or VI) of the first hair cycle

thick dermal layer ( J:70118 )

• at P14, the mutant back skin exhibits drastic thickening of the dermis

abnormal epidermis stratum basale morphology ( J:70118 )

• homozygotes display hyperproliferation of hair follicle epithelial cells and basal epidermal keratinocytes

hyperkeratosis ( J:70118 )

• hyperkeratosis is observed in the epidermis of back and tail skin of 3-month-old mutant mice

acanthosis ( J:70118 )

• acanthosis is observed in the epidermis of back and tail skin of 3-month-old mutant mice

epidermal hyperplasia ( J:70118 )

• hyperplasia is observed in the epidermis of back and tail skin of 3-month-old mutant mice

thick epidermis ( J:70118 )

• as early as P6, the mutant epidermis is already slightly thickened; no thickening is noted at P3

• at P20, the mutant skin still maintains the thickness of late catagen stages

• epidermal thickening is caused by hyperproliferation of basal keratinocytes

scaly skin ( J:70118 )

• at P7-P9, the skin of homozygotes has a squamous appearance

shiny skin ( J:70118 )

• at P7-P9, the skin of homozygotes has a shiny appearance

thick skin ( J:70118 )

cellular

increased keratinocyte proliferation ( J:70118 )

• homozygotes display hyperproliferation of basal epidermal keratinocytes while the number of apoptotic cells in the epidermis remains unaffected

renal/urinary system

renal/urinary system phenotype ( J:172774 )

N • normal kidney morphology is obseved

N • no cellular disorganization or enlargement of nuclei is seen in kidney proximal tubular cells

Genotype
MGI:4420985

hm3

• Allelic Composition: Ctsl^tm1Cptr/Ctsl^tm1Cptr
• Genetic Background: NOD.129P2-Ctsl^tm1Cptr

immune system

salivary gland inflammation ( J:153355 )

• sialadenitis is observed in both diabetic and nondiabetic mice at 6 months of age, however, number of lesions observed is less than number found in NOD mice (6.5 vs. 12-20)

decreased CD4-positive, alpha-beta T cell number ( J:153355 )

• number of CD4+ T cells is 3-fold reduced in thymus and lymph nodes as compared to NOD control

increased regulatory T cell number ( J:153355 )

• homozygotes exhibit a 2-fold increase in Foxp3-expressing T cells in comparison to heterozygotes

decreased susceptibility to autoimmune diabetes ( J:153355 )

• mice exhibit a complete resistance to diabetes

• adoptive transfer of GITR^hi-depleted Treg cells into NOD-Prkdc^scid host results in a diabetes incidence of 45.5%

endocrine/exocrine glands

salivary gland inflammation ( J:153355 )

• sialadenitis is observed in both diabetic and nondiabetic mice at 6 months of age, however, number of lesions observed is less than number found in NOD mice (6.5 vs. 12-20)

digestive/alimentary system

salivary gland inflammation ( J:153355 )

• sialadenitis is observed in both diabetic and nondiabetic mice at 6 months of age, however, number of lesions observed is less than number found in NOD mice (6.5 vs. 12-20)

hematopoietic system

decreased CD4-positive, alpha-beta T cell number ( J:153355 )

• number of CD4+ T cells is 3-fold reduced in thymus and lymph nodes as compared to NOD control

increased regulatory T cell number ( J:153355 )

• homozygotes exhibit a 2-fold increase in Foxp3-expressing T cells in comparison to heterozygotes

Genotype
MGI:4420986

ht4

• Allelic Composition: Ctsl^tm1Cptr/Ctsl⁺
• Genetic Background: NOD.129P2-Ctsl^tm1Cptr

immune system

insulitis ( J:153355 )

• insulitis scores for diabetic animals are similar to diabetic NOD controls

decreased susceptibility to autoimmune diabetes ( J:153355 )

• 55% of female mice exhibit blood glucose levels of greater than 250 mg/dl between 4-6 months of age as compared to 69% of NOD controls

• adoptive transfer of GITR^hi-depleted Treg cells into NOD-Prkdc^scid host results in a diabetes incidence of 41.7%

homeostasis/metabolism

hyperglycemia ( J:153355 )

• 55% of female mice exhibit blood glucose levels of greater than 250 mg/dl between 4-6 months of age as compared to 69% of NOD controls

endocrine/exocrine glands

insulitis ( J:153355 )

• insulitis scores for diabetic animals are similar to diabetic NOD controls

Genotype
MGI:3695741

cx5

• Allelic Composition: Ctsk^tm1Psa/Ctsk^tm1Psa; Ctsl^tm1Cptr/Ctsl^tm1Cptr
• Genetic Background: involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6J

endocrine/exocrine glands

abnormal thyroid gland morphology ( J:83877 )

• cells with enlarged lysosomes

abnormal thyroid follicle morphology ( J:83877 )

• 80% increase in size over controls

homeostasis/metabolism

abnormal thyroid hormone level ( J:83877 )

• 5-6 fold increases in thyroglobulin levels

decreased thyroxine level ( J:83877 )

• significantly reduced levels of free T4

decreased circulating thyroxine level ( J:83877 )

• deficient serum levels of T4

Genotype
MGI:3628482

cx6

• Allelic Composition: Ctsb^tm1Jde/Ctsb^tm1Jde; Ctsl^tm1Cptr/Ctsl^tm1Cptr
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J

Cerebral and cerebellar atrophy in Ctsb^tm1Jde/Ctsb^tm1Jde Ctsl^tm1Cptr/Ctsl^tm1Cptr mice

mortality/aging

postnatal lethality, incomplete penetrance ( J:77103 )

• most double homozygous mutant mice died around day 12

• the lifespan of double-mutant mice increased by several days when healthy littermates were removed at day 7

• with continuous nursing with wetted food twice daily, four double mutant mice survived the weaning period up to 50 days old

growth/size/body

postnatal growth retardation ( J:77103 )

• apparent growth impairment by day 7

• double homozygous mutant mice that survived the weaning period at 50 days old weighed less than half of the expected body weight

behavior/neurological

tremors ( J:77103 )

• double homozygous mutant mice that survived the weaning period demonstrated a mild unusual tremor and subtle rear limb spasticity

abnormal motor coordination/balance ( J:77103 )

• double homozygous mutant mice that survived the weaning period swayed backwards while grooming and used their tail for balance

decreased vertical activity ( J:77103 )

• double homozygous mutant mice that survived the weaning period demonstrated hesitating voluntary movements

nervous system

abnormal neuron apoptosis ( J:77103 )

• widespread TUNEL-positive staining in cerebral cortex and the cerebellar granule cell layer in brains of P23.5-24.5 mutant mice

abnormal hippocampus pyramidal cell layer ( J:77103 )

• the CA3 region of the stratum pyramidale was broadened and split

gliosis ( J:77103 )

• neuronal loss was paralleled by an increasing occurrence of hypertrophic astrocytes and Bergmann glia

neuron degeneration ( J:77103 )

• 50 days old mice exhibited pronounced cerebral and cerebellar atrophy

• molecular and internal granule cell layer were reduced and the Purkinje-cell layer had disappeared due to massive neuronal death in the cerebellar Purkinje- and granule-cell layers and the cerebral cortex during the third and fourth week of life

Purkinje cell degeneration ( J:77103 )

integument

delayed hair appearance ( J:77103 )

thick epidermis ( J:77103 )

• hyperproliferation of keratinocytes

cellular

abnormal neuron apoptosis ( J:77103 )

• widespread TUNEL-positive staining in cerebral cortex and the cerebellar granule cell layer in brains of P23.5-24.5 mutant mice