Phenotypes associated with this allele

• Allele Symbol: Pcsk2^tm1Dfs
• Allele Name: targeted mutation 1, Donald Steiner
• Allele ID: MGI:1857445
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Pcsk2^tm1Dfs/Pcsk2^tm1Dfs	B6;129-Pcsk2^tm1Dfs/J	MGI:5829028
hm2	Pcsk2^tm1Dfs/Pcsk2^tm1Dfs	involves: 129S1/Sv * 129X1/SvJ	MGI:5428027
hm3	Pcsk2^tm1Dfs/Pcsk2^tm1Dfs	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3054405
hm4	Pcsk2^tm1Dfs/Pcsk2^tm1Dfs	involves: 129S1/Sv * 129X1/SvJ * CD-1	MGI:3697813

Genotype
MGI:5829028

hm1

• Allelic Composition: Pcsk2^tm1Dfs/Pcsk2^tm1Dfs
• Genetic Background: B6;129-Pcsk2^tm1Dfs/J

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

cellular

abnormal pancreatic alpha cell differentiation ( J:236905 )

• increase in alpha-cell neogenesis, associated primarily with pancreatic duct(ule)s

renal/urinary system

dilated renal tubule ( J:236905 )

• variable but moderately severe atypical cortical tubular dilatation

endocrine/exocrine glands

abnormal pancreatic alpha cell morphology ( J:236905 )

• alpha-cells are often as large or larger than centrally placed beta-cells which are unaffected

• alpha cells have enlarged nuclei and irregular, often tortuous shape, prominent multiple nucleoli, abundant rough endoplasmic reticulum and secretory granule-packed cytoplasm

abnormal pancreatic alpha cell differentiation ( J:236905 )

• increase in alpha-cell neogenesis, associated primarily with pancreatic duct(ule)s

increased pancreatic alpha cell number ( J:236905 )

• hyperplastic alpha-cells

enlarged pancreatic islets ( J:236905 )

• islets are enlarged at 3 months of age

• atypical hyperplastic islets are present in the islet population at 12 and 18 months of age

• many mice show islets within which atypical hypertrophy and proliferation are seen as abundant, often columnar alpha-cells growing in folded, ribbon- or cord-like patterns about a tenuous fibrovascular core or blood-filled or open space

pancreatic islet hyperplasia ( J:236905 )

• islets display peripherally situated sheets of hypertrophic/hyperplastic alpha-cells with prominent karyomegaly, nuclear pleiomophism and occasionally, mitotic figures within hyperchromatic cytoplasm

increased pancreas tumor incidence ( J:236905 )

• mice develop islet adenomas and carcinomas by 6-8 months of age

• islet tumor incidence is greater in females than males, though the difference is not statistically significant

• incidence of islet adenomas is greater than that of carcinomas

• tumors primarily consist of alpha-cells associated to varying degrees with other islet endocrine cell types

• vascular invasion by tumor cells is seen and lymphatic vessels containing tumor cells are seen occasionally

• however, no pancreatic intraepithelial (ductal) neoplasia are seen

increased pancreatic islet cell adenoma incidence ( J:236905 )

• islet adenomas vary from being comprised of single-layered ribbon/tubular patterns to being double- or multiple-layered

increased glucagonoma incidence ( J:236511 )

increased pancreatic ductal adenocarcinoma incidence ( J:236905 )

• islet carcinomas are comprised of solid sheets of tumor cells

decreased glucagon secretion ( J:236905 )

• decrease in cellular glucagon level in islets

homeostasis/metabolism

decreased glucagon secretion ( J:236905 )

• decrease in cellular glucagon level in islets

decreased circulating glucagon level ( J:236905 )

• absence of circulating glucagon

• plasma proglucagon is increased at 3, 12, and 18 months of age

increased circulating insulin level ( J:236905 )

• plasma insulin levels are increased at 12 and 18 months of age

improved glucose tolerance ( J:236905 )

mortality/aging

premature death ( J:236905 )

• some mice die prematurely between 6.5 and 14 months of age

neoplasm

increased pancreas tumor incidence ( J:236905 )

• mice develop islet adenomas and carcinomas by 6-8 months of age

• islet tumor incidence is greater in females than males, though the difference is not statistically significant

• incidence of islet adenomas is greater than that of carcinomas

• tumors primarily consist of alpha-cells associated to varying degrees with other islet endocrine cell types

• vascular invasion by tumor cells is seen and lymphatic vessels containing tumor cells are seen occasionally

• however, no pancreatic intraepithelial (ductal) neoplasia are seen

increased pancreatic islet cell adenoma incidence ( J:236905 )

• islet adenomas vary from being comprised of single-layered ribbon/tubular patterns to being double- or multiple-layered

increased glucagonoma incidence ( J:236511 )

increased pancreatic ductal adenocarcinoma incidence ( J:236905 )

• islet carcinomas are comprised of solid sheets of tumor cells

Genotype
MGI:5428027

hm2

• Allelic Composition: Pcsk2^tm1Dfs/Pcsk2^tm1Dfs
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

mortality/aging

mortality/aging ( J:184882 )

N • mice exhibit normal survival in LPS-induced endotoxin shock

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:184882 )

N • mice exhibit normal response to LPS-induced endotoxin shock

Genotype
MGI:3054405

hm3

• Allelic Composition: Pcsk2^tm1Dfs/Pcsk2^tm1Dfs
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

cardiovascular system

increased systemic arterial blood pressure ( J:82967 )

• significantly increased blood pressure when placed on a high salt diet (158mmHg)

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:41505 )

abnormal pancreatic beta cell differentiation ( J:85590 )

• beta cells first appear functionally at E15 (2 days late)

increased pancreatic alpha cell mass ( J:41505 )

• increased volume of glucagon positive alpha cells

decreased pancreatic beta cell number ( J:41505 )

• modest reduction in beta cell numbers

increased pancreatic delta cell number ( J:41505 )

• increased number of somatostatin positive delta cells

abnormal gland physiology ( J:41505 )

• prohormone processing is incomplete

increased pancreatic alpha cell proliferation ( J:85590 )

• alpha cell proliferation at E17.5 3X normal

decreased glucagon secretion ( J:41505 )

• no mature glucagons formed

decreased insulin secretion ( J:41505 )

• limited formation of mature insulin

abnormal pancreatic somatostatin secretion ( J:41505 )

• limited maturation of somatostatin

homeostasis/metabolism

decreased glucagon secretion ( J:41505 )

• no mature glucagons formed

decreased insulin secretion ( J:41505 )

• limited formation of mature insulin

decreased circulating glucose level ( J:41505 )

• fasting blood sugar level was significantly reduced

decreased circulating insulin level ( J:41505 )

• low circulating insulin and elevated proinsulin

impaired glucose tolerance ( J:41505 )

• response to injected glucose was muted

decreased pituitary hormone level ( J:82967 )

• reduced levels of gamma-MSH in the pituitary on both high and low salt diet

reproductive system

reduced female fertility ( J:41505 )

♀ • females produced fewer consecutive litters

♀ • an increased number of pups were born dead

cellular

abnormal pancreatic beta cell differentiation ( J:85590 )

• beta cells first appear functionally at E15 (2 days late)

increased pancreatic alpha cell proliferation ( J:85590 )

• alpha cell proliferation at E17.5 3X normal

Genotype
MGI:3697813

hm4

• Allelic Composition: Pcsk2^tm1Dfs/Pcsk2^tm1Dfs
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * CD-1

behavior/neurological

hyporesponsive to tactile stimuli ( J:112641 )

• mutants show a higher latency in a mechanical nociception test (12 grams force vs baseline of 1.5 grams force to get response) 5 minutes following a warm swim

increased thermal nociceptive threshold ( J:112641 )

• mutants display higher latencies in tail-flick and hotplate tests 5 minutes following a warm swim (3 minutes at 33 degrees C)

• at 30 minutes after a warm swim, little difference compared to controls is seen

• mutants display higher latencies (1.5 fold x baseline) in hotplate tests 30 minutes following a cold swim (3 minutes at 10 degrees C) compared to controls (2-fold below baseline

• 5 minutes after a cold swim, both mutants and controls show similar increases above baseline for tail-flick and hot plate tests

analgesia ( J:112641 )

• mutants exhibit increased opiate-mediated stress-induced analgesia compared to wild-type at both spinal (tail-flick test) and supraspinal (mechanical and hotplate tests) levels