Phenotypes associated with this allele

• Allele Symbol: Terc^tm1Rdp
• Allele Name: targeted mutation 1, Ronald DePinho
• Allele ID: MGI:1857930
• Summary: 17 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Terc^tm1Rdp/Terc^tm1Rdp	B6J.Cg-Terc^tm1Rdp	MGI:5695524
hm2	Terc^tm1Rdp/Terc^tm1Rdp	involves: 129/Sv * C57BL/6 * C57BL/6J * SJL	MGI:4820640
hm3	Terc^tm1Rdp/Terc^tm1Rdp	involves: 129/Sv * C57BL/6J * SJL	MGI:2174766
hm4	Terc^tm1Rdp/Terc^tm1Rdp	involves: FVB/N	MGI:4365574
cx5	Dmd^mdx-4Cv/Dmd^mdx-4Cv Terc^tm1Rdp/Terc^tm1Rdp	B6.Cg-Terc^tm1Rdp Dmd^mdx-4Cv	MGI:5529018
cx6	Terc^tm1Rdp/Terc^tm1Rdp Tinf2^tm2.2Tdl/Tinf2^+	involves: 129 * BALB/cJ * C57BL/6 * SJL	MGI:5556401
cx7	Terc^tm1Rdp/Terc^tm1Rdp Terf1^tm1Tdl/Terf1^tm1Tdl	involves: 129S2/SvPas	MGI:2677844
cx8	Pms2^tm1Lisk/Pms2^tm1Lisk Terc^tm1Rdp/Terc^tm1Rdp	involves: 129/Sv * 129S2/SvPas * C57BL/6 * C57BL/6J * SJL	MGI:4820641
cx9	Pot1b^tm1.1Schg/Pot1b^tm1.1Schg Terc^tm1Rdp/Terc^tm1Rdp	involves: 129/Sv * 129S6/SvEvTac * C57BL/6 * SJL	MGI:3831883
cx10	Pot1b^tm1.1Schg/Pot1b^tm1.1Schg Terc^tm1Rdp/Terc^+	involves: 129/Sv * 129S6/SvEvTac * C57BL/6 * SJL	MGI:3831884
cx11	Terc^tm1Rdp/Terc^tm1Rdp Wrn^tm1Lgu/Wrn^tm1Lgu	involves: 129/Sv * BALB/c * C57BL/6 * SLJ	MGI:3700822
cx12	Terc^tm1Rdp/Terc^tm1Rdp Tg(KRT5-Tert)8043Blas/0	involves: 129/Sv * C57BL/6 * C57BL/6J * DBA/2 * SJL	MGI:3700845
cx13	Terc^tm1Rdp/Terc^tm1Rdp Tg(KRT5-Terf2)PMBlas/Y	involves: 129/Sv * C57BL/6 * CBA * SJL	MGI:6258421
cx14	Dmd^mdx/Y Terc^tm1Rdp/Terc^+	involves: 129/Sv * C57BL/6J * C57BL/10ScSn * SJL	MGI:4936867
cx15	Dmd^mdx/Y Terc^tm1Rdp/Terc^tm1Rdp	involves: 129/Sv * C57BL/6J * C57BL/10ScSn * SJL	MGI:4936865
cx16	Cdkn2a^tm1Rdp/Cdkn2a^+ Terc^tm1Rdp/Terc^tm1Rdp	involves: 129/Sv * C57BL/6J * SJL	MGI:3719054
cx17	Cdkn2a^tm1Rdp/Cdkn2a^tm1Rdp Terc^tm1Rdp/Terc^tm1Rdp	involves: 129/Sv * C57BL/6J * SJL	MGI:3719052

Genotype
MGI:5695524

hm1

• Allelic Composition: Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: B6J.Cg-Terc^tm1Rdp

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

skeleton

abnormal bone marrow morphology ( J:213181 )

• increase in bone marrow fat content in aged mice

decreased bone volume ( J:213181 )

• 41.7% and 84.9% decrease in femur bone volume at 3 months of age and in aged mice, respectively

abnormal compact bone morphology ( J:213181 )

• 27.1% and 49.3% increase in cortical porosity in young and aged mice, respectively

decreased compact bone area ( J:213181 )

• 4% and 28.2% decrease in cortical bone area in young and aged mice, respectively

decreased compact bone thickness ( J:213181 )

• decrease in cortical thickness in both young and aged mice

decreased bone trabecula number ( J:213181 )

• young femurs show a more rod-like trabecular structure

increased bone trabecular spacing ( J:213181 )

• increase in trabecular separation

decreased trabecular bone thickness ( J:213181 )

osteoporosis ( J:213181 )

• accelerated bone aging characteristic features of human senile osteoporosis

abnormal osteoid morphology ( J:213181 )

• osteoid significantly decreases with age

abnormal skeleton physiology ( J:213181 )

• bone shows mechanical alterations including an increase in structure model index, a decrease in anisotropy and a decrease in the moment of inertia

abnormal bone ossification ( J:213181 )

• mineralized surface, mineral apposition rate, and bone formation rate dramatically decline with age

adipose tissue

abnormal adipose tissue distribution ( J:213181 )

• increase in bone marrow fat content in aged mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
osteoporosis		DOID:11476	OMIM:166710	J:213181

Genotype
MGI:4820640

hm2

• Allelic Composition: Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: involves: 129/Sv * C57BL/6 * C57BL/6J * SJL

mortality/aging

premature death ( J:125218 )

• median survival is reduced in successive generations compared to in wild-type mice

digestive/alimentary system

increased enterocyte apoptosis ( J:125218 )

• regardless of generation

abnormal enterocyte proliferation ( J:125218 )

• intestinal cell proliferation is impaired compared to in wild-type mice

abnormal intestine morphology ( J:125218 )

• mice exhibit mild to severe intestinal atrophy unlike wild-type mice that worsens in successive generations

cellular

decreased telomere length ( J:125218 )

• telomeres become progressively shorter each generation unlike in wild-type mice

abnormal cell physiology ( J:125218 )

• mouse embryonic fibroblasts (MEFs) from third generation mice exhibit decreased immortalization ability under a 3T3 cell passage protocol compared with similarly treated wild-type cells

• sister chromatid exchange in MEFs is increased compared to in wild-type cells

increased enterocyte apoptosis ( J:125218 )

• regardless of generation

abnormal enterocyte proliferation ( J:125218 )

• intestinal cell proliferation is impaired compared to in wild-type mice

abnormal DNA repair ( J:125218 )

• cells from the small intestine exhibit an increase in gamma-H2AX foci, indicative of DNA damage, compared with cells from wild-type mice

chromosomal instability ( J:125218 )

• mouse embryonic fibroblasts (MEFs) exhibit in increase in microsatellite instability compared with wild-type cells

• end-to-end chromosome fusions in MEFs are increased compared to in wild-type cells

• MEFs from late generation mice exhibit an increase in chromosome breaks, fragments, bivalent recombination figures, and complex aberrations compared with wild-type cells

neoplasm

increased lymphoma incidence ( J:125218 )

• the incidence of lymphomas decreases in successive generation

homeostasis/metabolism

abnormal DNA repair ( J:125218 )

• cells from the small intestine exhibit an increase in gamma-H2AX foci, indicative of DNA damage, compared with cells from wild-type mice

Genotype
MGI:2174766

hm3

• Allelic Composition: Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: involves: 129/Sv * C57BL/6J * SJL

Axial/lateral elements of synaptonemal complexes and apoptosis of seminiferous tubules in Terc^tm1Rdp/Terc^tm1Rdp mice

mortality/aging

premature death ( J:110900 )

• older (6-8 months) fifth generation mutants that show sudden loss in body weight and activity die 7-12 hours after the manifestation of these phenotypes

prenatal lethality, incomplete penetrance ( J:53600 , J:89751 )

• a fraction of homozygous embryos from late generation homozygous matings do not survive gestation to completion or die immediately after birth (J:53600)

• only 74% of homozygous fetuses from late generation pregnant females are alive (J:89751)

premature aging ( J:120065 )

• late generation mutants exhibit accelerated degeneration as indicated by hair graying, alopecia, kyphosis, reduced body size and weight, and fragility

cellular

abnormal fetal cardiomyocyte proliferation ( J:110900 )

• second and fifth generation mutants exhibit decreased cardiac myocyte proliferation

abnormal oocyte morphology ( J:89751 )

♀ • the number of oocytes that form synaptonemal complexes is decreased

abnormal spermatocyte morphology ( J:89751 )

♂ • apoptosis is increased 5-fold in seminiferous tubules of G4 homozygotes; apoptosis is found in the outer layers of spermatocytes whereas the inner layer of spermatogonia remains intact

abnormal chromosome morphology ( J:89751 )

• lack of perinuclear distribution of telomeres in fourth generation mutants

abnormal telomere length ( J:43517 , J:60223 , J:74001 , J:89751 , J:96945 , J:110900 , J:120065 )

• embryonic fibroblast cells derived from mutant mice after the fourth generation lacked detectable telomeric repeats and were often aneupolid with chromosomal abnormalities, including end to end fusions (J:43517)

• splenocytes from non-immunized fifth generation mutants contain shorter telomere lengths than wild-type (J:60223)

• upon immunization with an antigen, proliferating splenocyte telomeres are shortened during germinal center formation, unlike in wildtype mice which show elongation of telomeres, however telomeres are longer than seen in non-immunized mutants (J:60223)

• telomere shortening occurs in both meiocytes with normal and abnormal synapsis (J:89751)

• keratinocytes exhibit a significant decrease in average telomere length compared with wild-type cells (J:96945)

• cardiac myocytes of second and fifth generation mutants show telomere shortening, with cardiomyocytes from older mutants having shorter telomeres than in younger mutants (J:110900)

• the anaphase bridge index (ABI) is increased in late-generation (G4/G5) intestinal crypts indicating telomere dysfunction (J:120065)

abnormal meiosis ( J:89751 )

• chromosome pairing, synapsis, and recombination are severely impaired in meiocytes with irregular telomeres

abnormal female meiosis ( J:89751 )

♀ • in response to telomere shortening, female germ cells arrest in early meiosis

♀ • meiocytes of fourth generation (G4) females with shortened telomeres bred with early generation males harboring relatively long telomeres, exhibit severely impaired chromosome pairing and synapsis and reduced meiotic recombination

♀ • synaptonemal complex protein 3 (SCP3) elements are altered in G4 female meiotic cells

abnormal male meiosis ( J:89751 )

♂ • the number of spermatocytes with synaptonemal complex protein 3 (SCP3) lateral elements is decreased in the fourth generation (G4) homozygotes

increased apoptosis ( J:120065 )

• apoptosis of male germ cells and in the GI crypts of late generation mutants

increased B cell apoptosis ( J:60223 )

• splenocytes from immunized fifth and sixth generation mice exhibit a small increase in apoptosis after mitogen treatment

increased cardiomyocyte apoptosis ( J:110900 )

• fifth generation mutants exhibit a 63% increase in cardiomyocyte apoptosis

increased embryonic tissue cell apoptosis ( J:53600 )

• E10.5 embryos with neural tube defects exhibit an increase in apoptosis

increased male germ cell apoptosis ( J:89751 , J:120065 )

♂ • in response to telomere shortening, male germ cells undergo apoptosis (J:89751)

♂ • apoptotic depletion of germ cells in late generation mutants (J:120065)

decreased B cell proliferation ( J:60223 )

• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens

decreased T cell proliferation ( J:60223 )

• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens

neoplasm

decreased incidence of induced tumors ( J:74001 )

• fifth generation mutants show decreased tumor growth rate and lower tumor formation efficiency upon dermal or subcutaneous melanoma cell injection

• tumors that are induced in fifth generation mutants show decreased replication potential and increased apoptotic rates

decreased incidence of tumors by chemical induction ( J:96945 )

• first generation mutants are slightly less susceptible to DMBA + TPA induced skin tumorigenesis, with a delay in papilloma formation compared to wild-type and papillomas that do not progress to lesions bigger than 8 mm

cardiovascular system

abnormal angiogenesis ( J:74001 )

• late generation mutants show decreased angiogenic potential in a basement membrane matrix assay

• microvessel density is decreased in the induced tumors of fifth generation mutants

• large abnormal vessels are present in the induced tumors of fifth generation mutants

abnormal myocardial fiber morphology ( J:110900 )

• the volume of binucleated cardiomyocytes is increased by 24% in second generation mutants and 52% in fifth generation mutants

• the volume of mononucleated cardiomyocytes is increased by 39% and 43% in second and fifth generation mutants, respectively

decreased myocardial fiber number ( J:110900 )

• cardiomyocyte number is decreased 16% and 49% in second and fifth generation mutants, respectively

decreased heart weight ( J:110900 )

• heart weight is decreased in fifth generation mutants

cardiac hypertrophy ( J:110900 )

• fifth generation mutants exhibit cardiac myocyte hypertrophy

heart left ventricle hypertrophy ( J:110900 )

• fifth generation mutants show a reduction in left ventricle mass that is accompanied by a decrease in left ventricle mass:chamber volume ratio, indicating decompensated eccentric left ventricle hypertrophy in the absence of an absolute increase in ventricular weight

decreased heart left ventricle weight ( J:110900 )

• left ventricle weight is decreased in fifth generation mutants

abnormal cardiovascular system physiology ( J:110900 )

• fifth generation, but not second generation, mutants suffer from a severe left ventricular failure

dilated cardiomyopathy ( J:110900 )

• dilated cardiomyopathy develops in fifth generation mutants

abnormal cardiac muscle contractility ( J:110900 )

• fifth generation, but not second generation, mutants exhibit a decrease in +dP/dt

abnormal cardiac muscle relaxation ( J:110900 )

• fifth generation mutants exhibit a decrease in -dP/dt

abnormal fetal cardiomyocyte proliferation ( J:110900 )

• second and fifth generation mutants exhibit decreased cardiac myocyte proliferation

decreased left ventricle developed pressure ( J:110900 )

• fifth generation mutants exhibit a decrease in LV developed pressure

increased left ventricle diastolic pressure ( J:110900 )

• fifth generation mutants exhibit an elevation of LV end-diastolic pressure

congestive heart failure ( J:110900 )

• older fifth generation mutants die of heart failure

hematopoietic system

increased B cell apoptosis ( J:60223 )

• splenocytes from immunized fifth and sixth generation mice exhibit a small increase in apoptosis after mitogen treatment

decreased B cell proliferation ( J:60223 )

• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens

decreased T cell proliferation ( J:60223 )

• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens

decreased spleen B cell follicle number ( J:60223 )

• spleens from sixth generation mutants (but not earlier generations) show fewer follicles

decreased spleen germinal center number ( J:60223 )

• fifth and sixth generation homozygotes show a reduction in germinal centers following antigen (KLH) immunization

immune system

increased B cell apoptosis ( J:60223 )

• splenocytes from immunized fifth and sixth generation mice exhibit a small increase in apoptosis after mitogen treatment

decreased B cell proliferation ( J:60223 )

• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens

decreased T cell proliferation ( J:60223 )

• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens

decreased spleen B cell follicle number ( J:60223 )

• spleens from sixth generation mutants (but not earlier generations) show fewer follicles

decreased spleen germinal center number ( J:60223 )

• fifth and sixth generation homozygotes show a reduction in germinal centers following antigen (KLH) immunization

embryo

increased embryonic tissue cell apoptosis ( J:53600 )

• E10.5 embryos with neural tube defects exhibit an increase in apoptosis

abnormal developmental patterning ( J:53600 )

• a portion of embryos with open neural tube show absence of bilateral symmetry in the brain

open neural tube ( J:53600 )

• a percentage of embryos fail to close the neural tube, particularly in the forebrain and midbrain, at E10.5; penetrance of this defect increases with generation number, with 30% of fifth generation embryos showing an open neural tube

nervous system

open neural tube ( J:53600 )

• a percentage of embryos fail to close the neural tube, particularly in the forebrain and midbrain, at E10.5; penetrance of this defect increases with generation number, with 30% of fifth generation embryos showing an open neural tube

reproductive system

abnormal oocyte morphology ( J:89751 )

♀ • the number of oocytes that form synaptonemal complexes is decreased

abnormal spermatocyte morphology ( J:89751 )

♂ • apoptosis is increased 5-fold in seminiferous tubules of G4 homozygotes; apoptosis is found in the outer layers of spermatocytes whereas the inner layer of spermatogonia remains intact

abnormal meiosis ( J:89751 )

• chromosome pairing, synapsis, and recombination are severely impaired in meiocytes with irregular telomeres

abnormal female meiosis ( J:89751 )

♀ • in response to telomere shortening, female germ cells arrest in early meiosis

♀ • meiocytes of fourth generation (G4) females with shortened telomeres bred with early generation males harboring relatively long telomeres, exhibit severely impaired chromosome pairing and synapsis and reduced meiotic recombination

♀ • synaptonemal complex protein 3 (SCP3) elements are altered in G4 female meiotic cells

abnormal male meiosis ( J:89751 )

♂ • the number of spermatocytes with synaptonemal complex protein 3 (SCP3) lateral elements is decreased in the fourth generation (G4) homozygotes

increased male germ cell apoptosis ( J:89751 , J:120065 )

♂ • in response to telomere shortening, male germ cells undergo apoptosis (J:89751)

♂ • apoptotic depletion of germ cells in late generation mutants (J:120065)

testicular atrophy ( J:120065 )

♂ • testicular atrophy and associated apoptotic depletion of germ cells in late generation mutants

reduced female fertility ( J:89751 )

♀ • late generation pregnant females have fewer fetuses

decreased litter size ( J:53600 )

• mutants of late generations show a decrease in litter size

infertility ( J:53600 )

• Background Sensitivity: mutants are infertile at the sixth generation (of interbreeding) and infertile at the fourth generation of backcrossing to C57BL/6J

behavior/neurological

decreased locomotor activity ( J:110900 )

• older (6-8 months) fifth generation mutants often show a sudden decrease in activity

growth/size/body

cardiac hypertrophy ( J:110900 )

• fifth generation mutants exhibit cardiac myocyte hypertrophy

heart left ventricle hypertrophy ( J:110900 )

• fifth generation mutants show a reduction in left ventricle mass that is accompanied by a decrease in left ventricle mass:chamber volume ratio, indicating decompensated eccentric left ventricle hypertrophy in the absence of an absolute increase in ventricular weight

decreased body size ( J:120065 )

• late generation mutants have reduced body size and are fragile

decreased body weight ( J:120065 )

• late generation mutants have reduced body weight

weight loss ( J:110900 )

• older (6-8 months) fifth generation mutants often show sudden losses in body weight

decreased fetal size ( J:89751 )

• 41% of homozygous fetuses from late generation pregnant females are reduced in size

muscle

abnormal myocardial fiber morphology ( J:110900 )

• the volume of binucleated cardiomyocytes is increased by 24% in second generation mutants and 52% in fifth generation mutants

• the volume of mononucleated cardiomyocytes is increased by 39% and 43% in second and fifth generation mutants, respectively

decreased myocardial fiber number ( J:110900 )

• cardiomyocyte number is decreased 16% and 49% in second and fifth generation mutants, respectively

heart left ventricle hypertrophy ( J:110900 )

• fifth generation mutants show a reduction in left ventricle mass that is accompanied by a decrease in left ventricle mass:chamber volume ratio, indicating decompensated eccentric left ventricle hypertrophy in the absence of an absolute increase in ventricular weight

dilated cardiomyopathy ( J:110900 )

• dilated cardiomyopathy develops in fifth generation mutants

abnormal cardiac muscle contractility ( J:110900 )

• fifth generation, but not second generation, mutants exhibit a decrease in +dP/dt

abnormal cardiac muscle relaxation ( J:110900 )

• fifth generation mutants exhibit a decrease in -dP/dt

abnormal fetal cardiomyocyte proliferation ( J:110900 )

• second and fifth generation mutants exhibit decreased cardiac myocyte proliferation

increased cardiomyocyte apoptosis ( J:110900 )

• fifth generation mutants exhibit a 63% increase in cardiomyocyte apoptosis

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:96945 )

N • homozygotes exhibit normal wound healing

decreased incidence of tumors by chemical induction ( J:96945 )

• first generation mutants are slightly less susceptible to DMBA + TPA induced skin tumorigenesis, with a delay in papilloma formation compared to wild-type and papillomas that do not progress to lesions bigger than 8 mm

digestive/alimentary system

abnormal intestine morphology ( J:120065 )

• the GI crypts of late generation mutants exhibit high levels of apoptosis

skeleton

kyphosis ( J:120065 )

• late generation mutants exhibit kyphosis

integument

alopecia ( J:120065 )

• late generation mutants exhibit alopecia

endocrine/exocrine glands

testicular atrophy ( J:120065 )

♂ • testicular atrophy and associated apoptotic depletion of germ cells in late generation mutants

Genotype
MGI:4365574

hm4

• Allelic Composition: Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: involves: FVB/N

cellular

abnormal spermatid morphology ( J:98586 )

♂ • at 8 months of age, second generation (G2) homozygotes exhibit fewer intact elongating spermatids containing extended telomeres than wild-type or heterozygous littermates

♂ • however, fertility is preserved, suggesting that alternative telomere extension activity is capable of partially complementing the telomerase defect

abnormal telomere length ( J:98586 )

• elongated spermatids from second generation (G2) homozygotes display variable telomere length, with some displaying long telomeres, while others have short telomeres

reproductive system

abnormal spermatid morphology ( J:98586 )

♂ • at 8 months of age, second generation (G2) homozygotes exhibit fewer intact elongating spermatids containing extended telomeres than wild-type or heterozygous littermates

♂ • however, fertility is preserved, suggesting that alternative telomere extension activity is capable of partially complementing the telomerase defect

Genotype
MGI:5529018

cx5

• Allelic Composition: Dmd^mdx-4Cv/Dmd^mdx-4Cv; Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: B6.Cg-Terc^tm1Rdp Dmd^mdx-4Cv

cardiovascular system

abnormal myocardial fiber morphology ( J:200365 )

♂ • cardiomyocyte nuclear area is moderately reduced in hearts of second generation (G2) 32 week old males as compared to controls

♂ • cardiomyocyte diameter is smaller in hearts of 32 week old G2 males

♂ • hearts from G2 males exhibit a loss of thick and thin myofilaments

increased heart left ventricle size ( J:200365 )

♂ • left ventricle enlargement is observed by 32 weeks in hearts of G2 males as compared to controls

dilated heart left ventricle ( J:200365 )

♂ • increased chamber size is observed in 32 week old G2 males as compared to controls

♂ • left ventricular transverse area is increased in diastole and systole in G2 males

cardiac fibrosis ( J:200365 )

♂ • ventricular fibrosis is observed by 32 weeks in hearts of G2 males

dilated cardiomyopathy ( J:200365 )

♂ • reduced cardiac function is observed in older G1 males (80 weeks), but is not observed at 32 weeks

♂ • cardiac dysfunction is observed at 8 weeks in third generation males

♂ • cardiac dysfunction can be induced by angiotension II infusion in younger second generation males

decreased heart ventricle muscle contractility ( J:200365 )

♂ • 32 week old G2 males exhibit reduced ventricular contractility as assessed by a reduction in fractional shortening as compared to controls

prolonged QRS complex duration ( J:200365 )

♂ • wide QRS interval is observed in both G1 and G2 males as compared to controls

ventricular cardiomyopathy ( J:200365 )

♂

cellular

decreased telomere length ( J:200365 )

♂ • 50% reduction in telomere length in G2 cardiomyocytes as compared to controls

♂ • however, telomere lengths are similar to controls in vascular smooth muscle cells

disorganized mitochondrial cristae ( J:200365 )

♂ • lack of well-defined cristae observed in cardiac muscle of second generation mice

abnormal mitochondrial shape ( J:200365 )

♂ • extensive mitochondrial fragmentation observed in cardiac muscle of second generation mice

decreased mitochondrial size ( J:200365 )

♂ • mitochondria size is decreaseed in cardiac muscle of second generation mice

increased mitochondrial number ( J:200365 )

♂ • moderately increased number of mitochondria is observed in cardiac muscle of second generation mice

oxidative stress ( J:200365 )

♂ • an increased number of 8-OHdg-positive nuclei, a marker of oxidative damage, is observed in G2 hearts as compared to controls

mortality/aging

premature death ( J:200365 )

♂ • death occurs as early as 30 weeks in first generation males, T50 is 120 weeks

♂ • death occurs as early as 19 weeks in second generation males, T50 is 80 weeks

muscle

abnormal myocardial fiber morphology ( J:200365 )

♂ • cardiomyocyte nuclear area is moderately reduced in hearts of second generation (G2) 32 week old males as compared to controls

♂ • cardiomyocyte diameter is smaller in hearts of 32 week old G2 males

♂ • hearts from G2 males exhibit a loss of thick and thin myofilaments

dilated cardiomyopathy ( J:200365 )

♂ • reduced cardiac function is observed in older G1 males (80 weeks), but is not observed at 32 weeks

♂ • cardiac dysfunction is observed at 8 weeks in third generation males

♂ • cardiac dysfunction can be induced by angiotension II infusion in younger second generation males

decreased heart ventricle muscle contractility ( J:200365 )

♂ • 32 week old G2 males exhibit reduced ventricular contractility as assessed by a reduction in fractional shortening as compared to controls

ventricular cardiomyopathy ( J:200365 )

♂

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Duchenne muscular dystrophy		DOID:11723	OMIM:310200	J:200365

Genotype
MGI:5556401

cx6

• Allelic Composition: Terc^tm1Rdp/Terc^tm1Rdp; Tinf2^tm2.2Tdl/Tinf2⁺
• Genetic Background: involves: 129 * BALB/cJ * C57BL/6 * SJL

cellular

abnormal chromosome morphology ( J:207367 )

• increase in chromosome ends without telomeric signals or signal loss from one of two sisters

decreased telomere length ( J:207367 )

• telomeres in bone marrow are shorter than homozygous Terc^tm1Rdp controls

• class of telomeres shorter than 15 kb is increased, while subfraction of longer telomeres is decreased

Genotype
MGI:2677844

cx7

• Allelic Composition: Terc^tm1Rdp/Terc^tm1Rdp; Terf1^tm1Tdl/Terf1^tm1Tdl
• Genetic Background: involves: 129S2/SvPas

mortality/aging

prenatal lethality, complete penetrance ( J:85440 )

• no homozygotes were born

Genotype
MGI:4820641

cx8

• Allelic Composition: Pms2^tm1Lisk/Pms2^tm1Lisk; Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: involves: 129/Sv * 129S2/SvPas * C57BL/6 * C57BL/6J * SJL

mortality/aging

mortality/aging ( J:125218 )

N • mice exhibit increased survival compared with single homozygotes

neoplasm

increased lymphoma incidence ( J:125218 )

• mice exhibit increased incidence of lymphomas compared with Terc^tm1Rdp homozygotes

• incidence of lymphomas decreases in successive generations

increased carcinoma incidence ( J:125218 )

• mice exhibit increased incidence of carcinomas compared with Terc^tm1Rdp homozygotes

• however, the incidence of carcinomas after three generations is normal

increased sarcoma incidence ( J:125218 )

• mice exhibit increased incidence of histiocytic sarcomas compared with Terc^tm1Rdp homozygotes

• however, the incidence of histiocytic sarcomas after three generations is normal

cellular

decreased telomere length ( J:125218 )

• telomeres in mouse embryonic fibroblasts or from small intestine sections become progressively shorter each generation compared to in cells from Terc^tm1Rdp homozygotes

abnormal cell physiology ( J:125218 )

• independent of telomere length, mouse embryonic fibroblasts (MEFs) undergo immortalization after fewer passages compared with cells from Terc^tm1Rdp homozygotes

• sister chromatid exchange in mouse embryonic fibroblasts is increased compared to in wild-type cells

increased enterocyte apoptosis ( J:125218 )

• compared with wild-type mice and third generation Terc^tm1Rdp homozygotes

abnormal DNA repair ( J:125218 )

• cells from the small intestine exhibit an increase in gamma-H2AX foci, indicative of DNA damage, compared with cells from wild-type mice

chromosomal instability ( J:125218 )

• mouse embryonic fibroblasts (MEFs) exhibit fewer chromosomal breaks and fragmentations compared with MEFs from Pms2^tm1Lisk

• MEFs exhibit in increase in microsatellite instability compared with wild-type cells

• end-to-end chromosome fusions in MEFs are increased compared to in cells from wild-type mice and Terc^tm1Rdp homozygotes

• however, mice exhibit rescue of increased bivalent recombination figures and chromatid cross-links observed in cells from Terc^tm1Rdp homozygotes and partial rescue of the complex chromosome aberrations, chromosomes fusions, and minichromosomes observed in cells from Pms2^tm1Lisk homozygotes

digestive/alimentary system

digestive/alimentary phenotype ( J:125218 )

N • unlike in Terc^tm1Rdp homozygotes, proliferation of intestinal cells is rescued after 2 generations

increased enterocyte apoptosis ( J:125218 )

• compared with wild-type mice and third generation Terc^tm1Rdp homozygotes

abnormal intestine morphology ( J:125218 )

• mice exhibit reduced intestinal atrophy compared with Terc^tm1Rdp homozygotes

homeostasis/metabolism

abnormal DNA repair ( J:125218 )

• cells from the small intestine exhibit an increase in gamma-H2AX foci, indicative of DNA damage, compared with cells from wild-type mice

Genotype
MGI:3831883

cx9

• Allelic Composition: Pot1b^tm1.1Schg/Pot1b^tm1.1Schg; Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: involves: 129/Sv * 129S6/SvEvTac * C57BL/6 * SJL

mortality/aging

postnatal lethality, complete penetrance ( J:144553 )

• all mice but one mouse born alive died within days of birth

• the single exception died by P13, all additional phenotype data is for this single mouse

reproductive system

decreased male germ cell number ( J:144553 )

♂ • near complete absence of germ cells representing all stages of spermatogenesis

abnormal spermatogenesis ( J:144553 )

♂ • near complete absence of all stages of spermatogenesis

hematopoietic system

absent bone marrow cell ( J:144553 )

• striking absence of bone marrow cells

• acute bone marrow failure

abnormal erythrocyte morphology ( J:144553 )

• dysplastic

abnormal granulocyte morphology ( J:144553 )

• dysplastic

pancytopenia ( J:144553 )

• severe

digestive/alimentary system

abnormal intestine morphology ( J:144553 )

• increased intestinal apoptosis

immune system

abnormal granulocyte morphology ( J:144553 )

• dysplastic

cellular

decreased male germ cell number ( J:144553 )

♂ • near complete absence of germ cells representing all stages of spermatogenesis

Genotype
MGI:3831884

cx10

• Allelic Composition: Pot1b^tm1.1Schg/Pot1b^tm1.1Schg; Terc^tm1Rdp/Terc⁺
• Genetic Background: involves: 129/Sv * 129S6/SvEvTac * C57BL/6 * SJL

mortality/aging

premature death ( J:144553 )

• overall median life span is 180 days

• median life span in males is 196 days while median life span for females is 84 days

cellular

decreased male germ cell number ( J:144553 )

♂ • male germ cell depletion

♂ • 3 fold decrease in testicular volume by 170 days of age

♂ • phenotype is more severe than in mice homozygous for the Pot1b mutation alone

increased apoptosis ( J:144553 )

• increased apoptosis in proliferative tissues and cells (male germ cells, hematopoietic cells, intestinal cells)

reproductive system

decreased male germ cell number ( J:144553 )

♂ • male germ cell depletion

♂ • 3 fold decrease in testicular volume by 170 days of age

♂ • phenotype is more severe than in mice homozygous for the Pot1b mutation alone

small testis ( J:144553 )

♂ • testicular atrophy

♂ • phenotype is more severe than in mice homozygous for the Pot1b mutation alone

abnormal spermatogenesis ( J:144553 )

♂ • near complete absence of all stages of spermatogenesis by 170 days of age

hematopoietic system

abnormal blood cell morphology/development ( J:144553 )

• primary bone marrow cells and splenocytes show increased numbers of fused chromosomes, significantly shorter telomeres, and increased numbers of signal free ends

abnormal definitive hematopoiesis ( J:144553 )

• 8 fold increase in apoptotic cells

anemia ( J:144553 )

• seen in females by 79 days of age

impaired hematopoiesis ( J:144553 )

• bone marrow shows a striking absence of trilineage hematopoiesis

• striking decrease in the size and number of colonies of myeloid cells formed by bone marrow cells

absent bone marrow cell ( J:144553 )

• bone marrow shows a striking absence of trilineage hematopoiesis which is almost completely replaced by stromal adipose tissue

• acute bone marrow failure

decreased erythrocyte cell number ( J:144553 )

• erythroid cells are reduced about 2 fold

abnormal granulocyte morphology ( J:144553 )

• granulocytes present are left-shifted with dysplatic features and immature blasts are present

decreased granulocyte number ( J:144553 )

• mature granulocytes are reduced about 4 fold

thrombocytopenia ( J:144553 )

• seen in females by 79 days of age

decreased leukocyte cell number ( J:144553 )

• by 79 days of age females develop severe leukopenia

• 60% of mice present with peripheral blood smears essentially devoid of leukocytes

decreased hematopoietic stem cell number ( J:144553 )

• results suggest renewal of hematopoietic stem cells is severely impaired

pigmentation

hyperpigmentation ( J:144553 )

• with age mice develop hyperpigmentation around their tails, legs, paws, and snout

• phenotype is more severe than in mice homozygous for the Pot1b mutation alone

growth/size/body

decreased body weight ( J:144553 )

• both sexes weigh less than littermate controls

• phenotype is more severe than in mice homozygous for the Pot1b mutation alone

digestive/alimentary system

abnormal crypts of Lieberkuhn morphology ( J:144553 )

• about a 25 fold increase in apoptotic cells in the intestinal crypt

• increase in apoptosis is accompanied by an increase in the anaphase bridge index

endocrine/exocrine glands

abnormal crypts of Lieberkuhn morphology ( J:144553 )

• about a 25 fold increase in apoptotic cells in the intestinal crypt

• increase in apoptosis is accompanied by an increase in the anaphase bridge index

small testis ( J:144553 )

♂ • testicular atrophy

♂ • phenotype is more severe than in mice homozygous for the Pot1b mutation alone

immune system

abnormal granulocyte morphology ( J:144553 )

• granulocytes present are left-shifted with dysplatic features and immature blasts are present

decreased granulocyte number ( J:144553 )

• mature granulocytes are reduced about 4 fold

decreased leukocyte cell number ( J:144553 )

• by 79 days of age females develop severe leukopenia

• 60% of mice present with peripheral blood smears essentially devoid of leukocytes

integument

abnormal nail morphology ( J:144553 )

• nail dystrophy

• phenotype is more severe than in mice homozygous for the Pot1b mutation alone

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
dyskeratosis congenita		DOID:2729	OMIM:PS127550	J:144553

Genotype
MGI:3700822

cx11

• Allelic Composition: Terc^tm1Rdp/Terc^tm1Rdp; Wrn^tm1Lgu/Wrn^tm1Lgu
• Genetic Background: involves: 129/Sv * BALB/c * C57BL/6 * SLJ

mortality/aging

premature death ( J:91715 )

• fourth to sixth generation (G4-G6) mutants have shorter median survival times than Terc homozygotes (24 weeks vs. 78 weeks)

• however, first and second generation (G1-G2) mutants have normal appearance, weight gain and lifespan

premature aging ( J:91715 )

• 12- to 16-week old fourth to sixth generation (G4-G6) mutants have clinical features of premature aging

growth/size/body

decreased body weight ( J:91715 )

• fourth to sixth generation (G4-G6) mutants have lower body weights, with a 20% reduction at 4 weeks of age and a 30% reduction at 32 weeks of age

cellular

abnormal chromosome morphology ( J:91715 )

• MEFs from G5 mutants exhibit an increase in chromosomal structural aberrations

• bone marrow metaphases derived from prematurely aged G4-G6 mutants show marked genomic instability, manifesting as more chromosomal p-p, p-q, and q-q arm fusions, and nonreciprocal translocations

decreased telomere length ( J:91715 )

• prematurely aged G4-G6 mutants exhibit accelerated loss of telomere length in primary bone marrow

homeostasis/metabolism

hyperglycemia ( J:91715 )

• 10 of 12 prematurely aged 20-week old G4-G6 mutants develop type II diabetes based on elevated fasting blood glucose levels, abnormal glucose tolerance tests and increased endogenous insulin levels

increased circulating insulin level ( J:91715 )

• prematurely aged 20-week old G4-G6 mutants show incresed endogenous insulin levels

impaired glucose tolerance ( J:91715 )

• prematurely aged 20-week old G4-G6 mutants show abnormal glucose tolerance tests

delayed wound healing ( J:91715 )

• 24-week old prematurely aged fifth generation mutants show delayed wound closure

impaired wound healing ( J:91715 )

• 24-week old prematurely aged fifth generation mutants show impaired healing of acute wounds, with delayed wound closure and fewer proliferating cells at the sites of wound re-epithelialization

skeleton

abnormal femur morphology ( J:91715 )

• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have femoral bones with decreased cortical thickness and trabecular mass

increased osteosarcoma incidence ( J:91715 )

• G1-G3 mutants routinely succumb to osteosarcomas and soft tissue sarcomas at around 63 weeks of age

kyphosis ( J:91715 )

• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have hunched spines

abnormal bone marrow morphology ( J:213181 )

• increase in bone marrow fat content in young and aged mice

decreased bone volume ( J:213181 )

• 47.6% and 69.8% decrease in femur bone volume at 3 months of age and in aged mice, respectively

abnormal compact bone morphology ( J:213181 )

• 19% and 60.1% increase in cortical porosity in young and aged mice, respectively

decreased compact bone area ( J:213181 )

• cortical bone area decreases with age, with a 29.7% decrease in aged mice

decreased compact bone thickness ( J:91715 , J:213181 )

• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have femoral bones with decreased cortical thickness (J:91715)

• decrease in cortical thickness in both young and aged mice (J:213181)

abnormal bone trabecula morphology ( J:213181 )

• young femurs show a more rod-like trabecular structure

decreased bone trabecula number ( J:213181 )

increased bone trabecular spacing ( J:213181 )

• increase in trabecular separation

decreased trabecular bone mass ( J:91715 )

• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have femoral bones with decreased trabecular mass

decreased trabecular bone thickness ( J:213181 )

• decrease in trabecular thickness that begins in young age and progresses with age

osteoporosis ( J:91715 , J:213181 )

• a proportion of G4-G6 mutants develop early-onset osteoporosis (J:91715)

• accelerated bone aging with characteristic features of human senile osteoporosis (J:213181)

abnormal osteoid morphology ( J:213181 )

• osteoid significantly decreases with age

abnormal skeleton physiology ( J:213181 )

• bone shows mechanical alterations including an increase in structure model index, a decrease in anisotropy and a decrease in the moment of inertia

abnormal bone ossification ( J:213181 )

• mineralized surface, mineral apposition rate, and bone formation rate dramatically decline with age

fragile skeleton ( J:91715 )

• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have bone fractures

vision/eye

cataract ( J:91715 )

• 12- to 16-week old f G4-G6 mutants develop cataracts

reproductive system

small gonad ( J:91715 )

• 12- to 16-week old G4-G6 mutants show severe hypogonadism

small testis ( J:91715 )

♂ • 20-week old G4-G6 mutants have small testes

neoplasm

increased sarcoma incidence ( J:91715 )

• although prematurely aged G4-G6 mutants are not prominently cancer-prone (as they die prematurely), G1-G3 mutants routinely succumb to osteosarcomas and soft tissue sarcomas at around 63 weeks of age

increased osteosarcoma incidence ( J:91715 )

• G1-G3 mutants routinely succumb to osteosarcomas and soft tissue sarcomas at around 63 weeks of age

digestive/alimentary system

abnormal crypts of Lieberkuhn morphology ( J:91715 )

• late-generation mutants have an increase in intestinal crypt cell apoptosis compared to Terc homozygotes

endocrine/exocrine glands

abnormal crypts of Lieberkuhn morphology ( J:91715 )

• late-generation mutants have an increase in intestinal crypt cell apoptosis compared to Terc homozygotes

small testis ( J:91715 )

♂ • 20-week old G4-G6 mutants have small testes

limbs/digits/tail

abnormal femur morphology ( J:91715 )

• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have femoral bones with decreased cortical thickness and trabecular mass

adipose tissue

decreased subcutaneous adipose tissue amount ( J:91715 )

• G4-G6 mutants exhibit a 43% reduction in subcutaneous adipose tissue at 4 months of age

abnormal adipose tissue distribution ( J:213181 )

• increase in bone marrow fat content in young and aged mice

integument

decreased subcutaneous adipose tissue amount ( J:91715 )

• G4-G6 mutants exhibit a 43% reduction in subcutaneous adipose tissue at 4 months of age

alopecia ( J:91715 )

• 12- to 16-week old G4-G6 mutants exhibit hair loss

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
osteoporosis		DOID:11476	OMIM:166710	J:213181
Werner syndrome		DOID:5688	OMIM:277700	J:91715

Genotype
MGI:3700845

cx12

• Allelic Composition: Terc^tm1Rdp/Terc^tm1Rdp; Tg(KRT5-Tert)8043Blas/0
• Genetic Background: involves: 129/Sv * C57BL/6 * C57BL/6J * DBA/2 * SJL

cellular

abnormal chromosome morphology ( J:96945 )

• mutants exhibit an increase in the frequency of chromosome aberrations in keratinocytes, in particular, of end-to-end fusions, breaks, and telomere associations

decreased telomere length ( J:96945 )

• keratinocytes exhibit a significant decrease in average telomere length compared with wild-type cells, similar to that seen in mutant Terc homozygotes

homeostasis/metabolism

decreased incidence of tumors by chemical induction ( J:96945 )

• mutants are less susceptible to DMBA + TPA induced skin tumorigenesis, with only 40% developing papillomas compared to 80%, 72% and 86% of wild-type, Tg(KRT5-Tert)8043Blas mutants, and Terc homozygous mutants, respectively

• the number of papillomas per mouse at week 15 is reduced compared to the above controls and papillomas never progress to lesions larger than 3 mm

delayed wound healing ( J:96945 )

• mutants exhibit a delayed rate of wound healing in skin compared to Tg(KRT5-Tert)8043Blas mutants

neoplasm

decreased incidence of tumors by chemical induction ( J:96945 )

• mutants are less susceptible to DMBA + TPA induced skin tumorigenesis, with only 40% developing papillomas compared to 80%, 72% and 86% of wild-type, Tg(KRT5-Tert)8043Blas mutants, and Terc homozygous mutants, respectively

• the number of papillomas per mouse at week 15 is reduced compared to the above controls and papillomas never progress to lesions larger than 3 mm

Genotype
MGI:6258421

cx13

• Allelic Composition: Terc^tm1Rdp/Terc^tm1Rdp; Tg(KRT5-Terf2)PMBlas/Y
• Genetic Background: involves: 129/Sv * C57BL/6 * CBA * SJL

integument

focal hair loss ( J:102653 )

• double mutant mice exhibit more severe hair loss in light-exposed areas than age-matched single Tg(KRT5-Terf2)PMBlas mutant mice

dry skin ( J:102653 )

• double mutant mice exhibit more severe skin dryness in light-exposed areas than age-matched single Tg(KRT5-Terf2)PMBlas mutant mice

cellular

decreased telomere length ( J:102653 )

• double mutant mice exhibit significantly shorter telomeres in tail skin than either single Tg(KRT5-Terf2)PMBlas mutant mice or single Terc^tm1Rdp homozygotes

Genotype
MGI:4936867

cx14

• Allelic Composition: Dmd^mdx/Y; Terc^tm1Rdp/Terc⁺
• Genetic Background: involves: 129/Sv * C57BL/6J * C57BL/10ScSn * SJL

muscle

centrally nucleated skeletal muscle fibers ( J:167294 )

♂

abnormal diaphragm morphology ( J:167294 )

♂ • diaphragms exhibit increased diameter compared with control mice

abnormal muscle physiology ( J:167294 )

♂ • muscle stem cell proliferation in undamaged muscles is higher than in control mice

homeostasis/metabolism

increased circulating creatine kinase level ( J:167294 )

♂ • with increasing age

Genotype
MGI:4936865

cx15

• Allelic Composition: Dmd^mdx/Y; Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: involves: 129/Sv * C57BL/6J * C57BL/10ScSn * SJL

mortality/aging

premature death ( J:167294 )

♂ • second generation mice beginning at 48 weeks of age likely due to respiratory failure

muscle

abnormal skeletal muscle morphology ( J:167294 )

♂ • first and second generation mice exhibit a progressive reduction in revertant myofiber cluster size compared to in control mice

increased variability of skeletal muscle fiber size ( J:167294 )

♂ • at 8 weeks in second generation mice

centrally nucleated skeletal muscle fibers ( J:167294 )

♂ • in first and second generation mice

abnormal diaphragm morphology ( J:167294 )

♂ • diaphragms in first and second generation mice exhibit increased diameter compared with control mice

♂ • by 76 weeks, diaphragm muscle is atrophied unlike in control mice

decreased satellite cell number ( J:167294 )

♂ • in aged second generation mice

skeletal muscle degeneration ( J:167294 )

♂ • in second generation mice with age

skeletal muscle fibrosis ( J:167294 )

♂ • in second generation mice

skeletal muscle necrosis ( J:167294 )

♂ • at 8 weeks in second generation mice

calcified muscle ( J:167294 )

♂ • second generation mice exhibit calcium depositions in the muscles unlike control mice

dystrophic muscle ( J:167294 )

♂ • second generation mice exhibit progressive muscular dystrophy with age unlike control mice

♂ • however, dystrophic phenotypes are improved by transplantation with wild-type muscle stem cells

muscular atrophy ( J:167294 )

♂ • in first and second generation mice prior to and after damage

abnormal muscle physiology ( J:167294 )

♂ • at 8 weeks, second generation mice exhibit increased myofiber membrane permeability compared with control mice

♂ • second generation mice exhibit impaired muscle stem cell proliferation compared with control mice

♂ • muscle stem cells from second generation mice exhibit impaired proliferative potential in culture compared with control cells

♂ • muscle stem cells from second generation mice exhibit impaired engrafting after transplantation compared with control cells

myositis ( J:167294 )

♂ • at 8 weeks in second generation mice

abnormal muscle electrophysiology ( J:167294 )

♂ • at 8 weeks, first and second generation mice exhibit decreased muscle twitch force, tetanic force, and tetanic tension compared with control mice

muscle weakness ( J:167294 )

♂ • at 8 weeks, second generation mice spend less time running on a treadmill than control mice

♂ • at 8 weeks, second generation mice hold onto a grid for less time than control mice

homeostasis/metabolism

impaired exercise endurance ( J:167294 )

♂ • at 8 weeks, second generation mice spend less time running on a treadmill than control mice

increased circulating creatine kinase level ( J:167294 )

♂ • at 8 weeks in second generation mice, but declining after 60 weeks of age

cellular

decreased telomere length ( J:167294 )

♂ • myoblasts from first and second generation exhibit shortened telomeres compared with control cells

chromosomal instability ( J:167294 )

♂ • myoblasts from first and second generation exhibit fused chromosomes unlike control cells

skeleton

kyphosis ( J:167294 )

♂ • in aged second generation mice

respiratory system

respiratory failure ( J:167294 )

♂ • second generation mice beginning at 48 weeks of age likely due to respiratory failure

immune system

myositis ( J:167294 )

♂ • at 8 weeks in second generation mice

behavior/neurological

impaired exercise endurance ( J:167294 )

♂ • at 8 weeks, second generation mice spend less time running on a treadmill than control mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Duchenne muscular dystrophy		DOID:11723	OMIM:310200	J:167294

Genotype
MGI:3719054

cx16

• Allelic Composition: Cdkn2a^tm1Rdp/Cdkn2a⁺; Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: involves: 129/Sv * C57BL/6J * SJL

neoplasm

increased tumor incidence ( J:120065 )

• 84% of early generation mutants succumb to tumors with a median tumor-free latency of 71.6 weeks

• late generation mutants show a decrease in percent tumor death and an increase in tumor-free latency, from 84% to 20% and 71.6-104.9 weeks

increased lymphoma incidence ( J:120065 )

• 19% and 23% of early generation and late generation mutants, respectively, develop lymphomas

increased sarcoma incidence ( J:120065 )

• 35% and 39% of early generation and late generation mutants, respectively, develop histocytic sarcomas

• 20% and 23% of early generation and late generation mutants, respectively, develop soft tissue sarcomas

Genotype
MGI:3719052

cx17

• Allelic Composition: Cdkn2a^tm1Rdp/Cdkn2a^tm1Rdp; Terc^tm1Rdp/Terc^tm1Rdp
• Genetic Background: involves: 129/Sv * C57BL/6J * SJL

Degenerative phenotypes, including increased apoptosis in gastrointestinal crypts and germ cell depletion, in Terc^tm1Rdp/Terc^tm1Rdp and Cdkn2a^tm1Rdp/Cdkn2a^tm1Rdp Terc^tm1Rdp/Terc^tm1Rdp mice

mortality/aging

premature aging ( J:120065 )

• 12- to 13-week old late generation (G4) mutants exhibit accelerated degeneration as indicated by hair graying, alopecia, kyphosis, reduced body size and weight, and fragility

neoplasm

increased tumor incidence ( J:120065 )

• 98% of early generation mutants succumb to tumors with a median tumor-free latency of 38.6 weeks

• late generation mutants show a decrease in percent tumor death and an increase in tumor-free latency, from 98% to 43% and 38.6-65.3 weeks compared to early generation mutants

increased lymphoma incidence ( J:120065 )

• 11% and 10% of early generation and late generation mutants, respectively, develop lymphomas

increased sarcoma incidence ( J:120065 )

• 57% and 59% of early generation and late generation mutants, respectively, develop histocytic sarcomas

• 24% and 28% of early generation and late generation mutants, respectively, develop soft tissue sarcomas

cellular

abnormal telomere length ( J:120065 )

• the anaphase bridge index (ABI) is increased to the same extent as in Terc^tm1Rdp homozygotes in late-generation (G4/G5) intestinal crypts indicating telomere dysfunction

increased male germ cell apoptosis ( J:120065 )

♂ • apoptotic depletion of germ cells in late generation mutants

decreased cell proliferation ( J:120065 )

• MEFs grown in culture show decreased growth rates after 10 population doublings with steady slow proliferation thereafter, indicating that telomere dysfunction suppresses the growth rate

• early generation (G0) astrocytes show continuous proliferation whereas the late generation (G4) astrocytes senesce after 2.5 population doublings, indicating that telomere dysfunction constrains the immortalization potential of astrocytes

reproductive system

increased male germ cell apoptosis ( J:120065 )

♂ • apoptotic depletion of germ cells in late generation mutants

testicular atrophy ( J:120065 )

♂ • testicular atrophy and associated apoptotic depletion of germ cells in late generation mutants

growth/size/body

decreased body size ( J:120065 )

• late generation mutants have reduced body size and are fragile

decreased body weight ( J:120065 )

• late generation mutants have reduced body weight

digestive/alimentary system

abnormal intestine morphology ( J:120065 )

• the GI crypts of late generation mutants exhibit high levels of apoptosis

skeleton

kyphosis ( J:120065 )

• late generation mutants exhibit kyphosis

endocrine/exocrine glands

testicular atrophy ( J:120065 )

♂ • testicular atrophy and associated apoptotic depletion of germ cells in late generation mutants