Phenotypes associated with this allele

• Allele Symbol: Wrn^tm1Lgu
• Allele Name: targeted mutation 1, Leonard Guarente
• Allele ID: MGI:2386438
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Wrn^tm1Lgu/Wrn^tm1Lgu	B6J.Cg-Wrn^tm1Lgu	MGI:5695526
hm2	Wrn^tm1Lgu/Wrn^tm1Lgu	involves: BALB/c	MGI:3700820
cx3	Trp53^tm1Tyj/Trp53^tm1Tyj Wrn^tm1Lgu/Wrn^tm1Lgu	involves: 129S2/SvPas * BALB/c	MGI:3700821
cx4	Terc^tm1Rdp/Terc^tm1Rdp Wrn^tm1Lgu/Wrn^tm1Lgu	involves: 129/Sv * BALB/c * C57BL/6 * SLJ	MGI:3700822

Genotype
MGI:5695526

hm1

• Allelic Composition: Wrn^tm1Lgu/Wrn^tm1Lgu
• Genetic Background: B6J.Cg-Wrn^tm1Lgu

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

hematopoietic system

increased osteoclast cell number ( J:213181 )

• increase in osteoclast number with age

immune system

increased osteoclast cell number ( J:213181 )

• increase in osteoclast number with age

skeleton

increased osteoclast cell number ( J:213181 )

• increase in osteoclast number with age

decreased bone volume ( J:213181 )

• 46.4% decrease in femur bone volume in aged mice

Genotype
MGI:3700820

hm2

• Allelic Composition: Wrn^tm1Lgu/Wrn^tm1Lgu
• Genetic Background: involves: BALB/c

cellular

abnormal cell physiology ( J:61567 )

• homozygous fibroblasts senesce approximately one passage earlier than controls

• however, homozygotes do not show any overt histological signs of accelerated senescence, are capable of living beyond 2 years of age, and cells do not show increased susceptibility to the genotoxins camptothecin or 4-NQO

Genotype
MGI:3700821

cx3

• Allelic Composition: Trp53^tm1Tyj/Trp53^tm1Tyj; Wrn^tm1Lgu/Wrn^tm1Lgu
• Genetic Background: involves: 129S2/SvPas * BALB/c

mortality/aging

premature death ( J:61567 )

• double mutants exhibit increased mortality rate (life span of 122 days) relative to mice homozygous for Trp53^tm1Tyj and heterozygous for Wrn^tm1Lgu (life span of 149 days)

Genotype
MGI:3700822

cx4

• 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