Inducing a Human Disease
Humanization with Human Mutant Genes
Genomics studies provide statistical correlation between the presence of mutations and the pathology (onset, development, lethality, etc.) which does not present evidence of causality. The generation of mouse models displaying a substitution of the wild-type mouse gene by a mutant version (mouse or human) enables the study of mutation roles in the disease and, consequently, the mechanisms of disease etiology and progression.
Case study: Inducing a human disease in mice - Paget's disease-like disorder.
Adapted from Daroszewska et al. Hum Mol Genet 2011. A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget's disease-like disorder in mice.
Model Recapitulates Human Disease
Mice presenting the human point mutation P394L develop a Paget's disease-like disorder.
MicroCT analysis of long bones from P394L mutant and wild-type (WT) mice. Mutant mice are showing multiple focal osteolytic lesions penetrating the cortex (arrows).
Axial microCT image of lumbar vertebra 5.
(N) WT mouse showing normal morphology and trabecular structure.
(O) P394L+/+ mouse showing an osteosclerotic lesion replacing most of the vertebral body.