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Phenotypes Associated with This Genotype
Genotype
MGI:3700822
Allelic
Composition
Terctm1Rdp/Terctm1Rdp
Wrntm1Lgu/Wrntm1Lgu
Genetic
Background
involves: 129/Sv * BALB/c * C57BL/6 * SLJ
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Terctm1Rdp mutation (4 available); any Terc mutation (5 available)
Wrntm1Lgu mutation (1 available); any Wrn mutation (7 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• 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
• 12- to 16-week old fourth to sixth generation (G4-G6) mutants have clinical features of premature aging

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

homeostasis/metabolism
• 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
• prematurely aged 20-week old G4-G6 mutants show incresed endogenous insulin levels
• prematurely aged 20-week old G4-G6 mutants show abnormal glucose tolerance tests
• 24-week old prematurely aged fifth generation mutants show delayed wound closure
• 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
• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have femoral bones with decreased cortical thickness and trabecular mass
• G1-G3 mutants routinely succumb to osteosarcomas and soft tissue sarcomas at around 63 weeks of age
• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have hunched spines
• increase in bone marrow fat content in young and aged mice
• 47.6% and 69.8% decrease in femur bone volume at 3 months of age and in aged mice, respectively
• 19% and 60.1% increase in cortical porosity in young and aged mice, respectively
• cortical bone area decreases with age, with a 29.7% decrease in aged mice
• 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)
• young femurs show a more rod-like trabecular structure
• increase in trabecular separation
• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have femoral bones with decreased trabecular mass
• decrease in trabecular thickness that begins in young age and progresses with age
• a proportion of G4-G6 mutants develop early-onset osteoporosis (J:91715)
• accelerated bone aging with characteristic features of human senile osteoporosis (J:213181)
• osteoid significantly decreases with age
• bone shows mechanical alterations including an increase in structure model index, a decrease in anisotropy and a decrease in the moment of inertia
• mineralized surface, mineral apposition rate, and bone formation rate dramatically decline with age
• by 32 weeks of age, all G4-G6 mutants showing signs of premature aging have bone fractures

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

reproductive system
• 12- to 16-week old G4-G6 mutants show severe hypogonadism
• 20-week old G4-G6 mutants have small testes

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

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

endocrine/exocrine glands
• late-generation mutants have an increase in intestinal crypt cell apoptosis compared to Terc homozygotes
• 20-week old G4-G6 mutants have small testes

limbs/digits/tail
• 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
• G4-G6 mutants exhibit a 43% reduction in subcutaneous adipose tissue at 4 months of age
• increase in bone marrow fat content in young and aged mice

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


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB), Gene Ontology (GO)
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last database update
03/31/2020
MGI 6.15
The Jackson Laboratory