Analysis Tools
cellular
|
• primary cultures of osteoblasts isolated from mutant calvaria exhibit an 8-fold elevation in procollagen levels; this may lead to accumulation of procollagen and distention of ER cisternae
|
|
• some mutant osteoblasts exhibit pycnotic nuclei and other signs of apoptosis
|
mortality/aging
|
• at least 23% of homozygotes die within the first 48 hrs
• only 37% of the expected number survive beyond the first few days
|
|
• ~30% to 40% of homozygotes die prenatally
|
growth/size/body
|
• at P7 and at 4 weeks of age, homozygotes are ~40% to 50% smaller than wild-type mice
|
|
• surviving newborns are of normal size but display severe postnatal growth retardation up to 4 weeks of age
|
homeostasis/metabolism
|
• at P17, the total insulin content in pancreatic islets is reduced by 32%; however, beta cell loss is partially compensated for by a >2-fold expression of insulin in the remaining cells
|
hyperglycemia
(
J:76661
)
|
• homozygotes are euglycemic for the first 3 weeks but rapidly become diabetic, with severe hyperglycemia first noted at ~P22
• at >P22, blood glucose levels often exceed the detection capability of the blood glucose monitor
• onset of diabetes correlates with loss of insulin-producing beta cells in pancreatic islets
|
|
• at P7-P11, prediabetic homozygotes display 70% of wild-type pancreatic insulin but have serum insulin levels indistinguishable from those in wild-type mice
• by 2 months, diabetic homozygotes display 10% of wild-type pancreatic insulin and only 5% of wild-type serum insulin levels
|
|
• diabetic homozygotes are incapable of rapidly clearing blood glucose
|
|
• diabetic homozygotes exhibit a 3-fold increase in liver glycogen content relative to non-diabetic wild-type mice
|
endocrine/exocrine glands
|
• at 3 weeks, many pancreatic acinar cells display a fragmented and distended endoplasmic reticulum that is devoid of protein in the cisternae, with crowding of zymogen granules around the nucleus
• by 4 weeks, the pancreatic acini of some homozygotes succumb to massive apoptosis, appear highly vacuolated, and lack zymogen granules; an increase in periacinar fibroblast-like cells is observed
|
|
• at P11-P12, prediabetic homozygotes show significantly reduced levels of pancreatic alpha-amylase, lipase, carboxypeptidase A, DNase, and RNase relative to wild-type mice; in contrast, carboxypeptidase B and trypsinogen levels remain unaffected
• at P26-P28, diabetic homozygotes exhibit similarly reduced levels of alpha-amylase, carboxypeptidase A, and lipase
|
|
• by P14, alpha cells outnumber the beta cells in mutant islets; however, the number of glucagon-secreting alpha cells is rapidly reduced at >4 weeks after birth
|
|
• no glucagon-secreting alpha cells are detected at 6 weeks after birth
|
|
• by P14, homozygotes exhibit progressive apoptotic loss of beta cells, with very few insulin-secreting beta cells noted at 4 weeks after birth
(J:76661)
|
|
• no insulin-secreting beta cells are detected at 6 weeks after birth
|
|
• at >4 weeks after birth, the overall size of the mutant islet is severely reduced
|
|
• at P17, the total insulin content in pancreatic islets is reduced by 32%; however, beta cell loss is partially compensated for by a >2-fold expression of insulin in the remaining cells
|
digestive/alimentary system
|
• at 3 weeks, many pancreatic acinar cells display a fragmented and distended endoplasmic reticulum that is devoid of protein in the cisternae, with crowding of zymogen granules around the nucleus
• by 4 weeks, the pancreatic acini of some homozygotes succumb to massive apoptosis, appear highly vacuolated, and lack zymogen granules; an increase in periacinar fibroblast-like cells is observed
|
|
• at P11-P12, prediabetic homozygotes show significantly reduced levels of pancreatic alpha-amylase, lipase, carboxypeptidase A, DNase, and RNase relative to wild-type mice; in contrast, carboxypeptidase B and trypsinogen levels remain unaffected
• at P26-P28, diabetic homozygotes exhibit similarly reduced levels of alpha-amylase, carboxypeptidase A, and lipase
|
skeleton
|
• primary cultures of osteoblasts isolated from mutant calvaria exhibit an 8-fold elevation in procollagen levels; this may lead to accumulation of procollagen and distention of ER cisternae
|
|
• some mutant osteoblasts exhibit pycnotic nuclei and other signs of apoptosis
|
|
• newborn homozygotes exhibit severe dysplasias in the axial skeleton (also observed prenatally, data not shown)
|
|
• homozygotes exhibit asymmetrical formation and compression of the vertebral column
|
|
• homozygotes exhibit defective compact bone formation in both long bone and flat bone types, with large perforations and discontinuities in long bone collars, parietal bones of the skull, and the body of vertebrae
|
|
• the compact bone of mutant vertebrae is often significantly thinner or even absent in some cases
|
|
• many, but not all, mutant osteoblasts display highly distended and fragmented rough endoplasmic reticulum (ER)
• some mutant osteoblasts exhibit pycnotic nuclei and other signs of apoptosis
• unlike the protein-depleted ER cisternae of mutant acinar cells, the fragmented ER cisternae of mutant osteoblasts are rich in protein
|
osteoporosis
(
J:76661
)
|
• homozygotes display reduced bone mineralization of the entire skeleton in bone tissues derived from both intramembranous and endochondral ossification
|
behavior/neurological
|
• homozygotes exhibit severe spinal curvature
|
|
• homozygotes display reduced locomotor activity
|
limbs/digits/tail
|
• homozygotes display splayed hindlimbs
|
liver/biliary system
|
• diabetic homozygotes exhibit a 3-fold increase in liver glycogen content relative to non-diabetic wild-type mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Wolcott-Rallison syndrome | DOID:0090060 |
OMIM:226980 |
J:76661 | |
