Irs3<tm1Lhd> Targeted Allele Detail MGI Mouse (MGI:2149647)

Irs3^tm1Lhd
Targeted Allele Detail

Nomenclature

Symbol:	Irs3^tm1Lhd
Name:	insulin receptor substrate 3; targeted mutation 1, Gustav E Lienhard
MGI ID:	MGI:2149647
Synonyms:	IRS-3^-/-, IRS3-
Gene:	Irs3 Location: Chr5:138084260-138086942 bp, - strand Genetic Position: Chr5, cytoband G2

Mutation
origin

Germline Transmission:	Earliest citation of germline transmission: J:55667
Parent Cell Line:	J1 (ES Cell)
Strain of Origin:	129S4/SvJae

Mutation
description

Allele Type:	Targeted (knock-out)
Mutation:	Insertion
	A neomycin resistance cassette disrupted the coding region of the gene. (J:55667)

Find Mice (IMSR)

Mouse strains and cell lines available from the International Mouse Strain Resource (IMSR)

Carrying this Mutation:	Mouse Strains: 1 strain available Cell Lines: 0 lines available
Carrying any Irs3 Mutation:	1 strain or line available

Phenotype
summary

Phenotype Summary by Mammalian Phenotype terms

(show or hide all annotated terms)

Genotypes are listed in the next section.

Key:

hm	homozygous	ht	heterozygous
cn	conditional genotype	cx	complex: > 1 genome feature
tg	involves transgenes	ot	other: hemizygous, indeterminate,...
N	normal phenotype		expected model not found

Affected Systems	Genotypes:	hm1	cx2
adipose tissue			√
decreased white adipose tissue amount			√
abnormal gonadal fat pad morphology			√
		hm1	cx2
digestive/alimentary system			√
increased pancreatic beta cell mass			√
pancreatic islet hyperplasia			√
		hm1	cx2
endocrine/exocrine glands			√
increased pancreatic beta cell mass			√
pancreatic islet hyperplasia			√
		hm1	cx2
growth/size			√
postnatal growth retardation			√
		hm1	cx2
homeostasis/metabolism			√
hyperglycemia			√
increased circulating insulin level			√
decreased circulating leptin level			√
decreased circulating free fatty acid level			√
impaired glucose tolerance			√
insulin resistance			√
decreased triglyceride level			√
decreased circulating triglyceride level			√
		hm1	cx2
lethality/prenatal-perinatal			N
lethality/prenatal-perinatal phenotype			N
		hm1	cx2
liver/biliary system			N
liver/biliary system phenotype			N
		hm1	cx2
normal phenotype		N
no abnormal phenotype detected		N

Phenotypic
data by
genotype

Phenotypic Data by Genotype

(show or hide all phenotypic details)

Genotype	Allelic Composition	Genetic Background
hm1	Irs3^tm1Lhd/Irs3^tm1Lhd	involves: 129S4/SvJae * C57BL/6
normal phenotype no abnormal phenotype detected (J:55667) in general, homozygotes are viable, fertile and display normal growth and development as well as normal glucose homeostasis and normal insulin-stimulated glucose transport in adipocytes at 9-13 weeks of age, young male homozygotes show fasting plasma insulin levels that are 60% of wild-type levels; however, this difference is no longer apparent at 6 months
Genotype	Allelic Composition	Genetic Background
cx2	Irs1^tm1Jos/Irs1^tm1Jos Irs3^tm1Lhd/Irs3^tm1Lhd	involves: 129S2/SvPas * 129S4/SvJae * C57BL/6
lethality/prenatal-perinatal lethality-prenatal/perinatal (J:80976) double mutant progeny are obtained at about half the expected frequency (3.4% vs. 6.25%), suggesting increased prenatal and/or early postnatal lethality growth/size postnatal growth retardation (J:80976) double homozygous males and females show severe growth retardation throughout life relative to wild-type mice homeostasis/metabolism hyperglycemia (J:80976) as early as 5 weeks, double homozygotes show increased blood glucose levels in both the fasted and the fed states notably, injection of leptin adenovirus leads to normalization of blood glucose levels in double mutant but not in wild-type mice increased circulating insulin level (J:80976) as early as 5 weeks, double homozygotes show increased plasma insulin levels in both the fasted and fed states notably, injection of leptin adenovirus leads to normalization of plasma insulin levels in double mutant but not in wild-type mice decreased circulating leptin level (J:80976) in 2-month-old double homozygotes, fed plasma leptin levels are reduced relative to wild-type and single mutant mice; fasted plasma leptin levels are also reduced, albeit to a lesser extent than in the fed state decreased circulating free fatty acid level (J:80976) at 2 months, fasted plasma free fatty acid levels are significantly reduced in both male and female double homozygotes relative to wild-type mice, and in double homozygous males relative to Irs1^tm1Jos and Irs3^tm1Lhd mice impaired glucose tolerance (J:80976) at 6 weeks, double homozygous males exhibit significant glucose intolerance insulin resistance (J:80976) at 6 weeks, double homozygous males exhibit severe insulin resistance decreased triglyceride level (J:80976) in double homozygous males, whole-body triglyceride content is reduced by ~75%, ~45%, and ~70% relative to wild-type, Irs1^tm1Jos, and Irs3^tm1Lhd mice, respectively decreased circulating triglyceride level (J:80976) at 2 months, fasted plasma triglyceride levels are markedly reduced in both male and female double homozygotes relative to wild-type and Irs3^tm1Lhd mice, and in double homozygous females relative to Irs1^tm1Jos mice although double mutant livers tend to contain less triglycerides than wild-type livers, this difference is statistically insignificant; skeletal muscle triglyceride content remains normal adipose tissue decreased white adipose tissue amount (J:80976) in double homozygotes, perigonadal (white) fat pad mass is decreased by ~95%, ~80%, and ~85% relative to wild-type, Irs1^tm1Jos, and Irs3^tm1Lhd mice, respectively in contrast, the interscapular brown fat pad appears unaffected with respect to color and size notably, injection of leptin adenovirus leads to a further reduction in white adipose tissue mass (reduced perigonadal fat pads); no significant body weight changes are observed abnormal gonadal fat pad morphology (J:80976) double homozygotes exhibit reduced adipocyte size of perigonadal fat pads relative to wild-type, Irs1^tm1Jos and Irs3^tm1Lhd mice endocrine/exocrine glands increased pancreatic beta cell mass (J:80976) double homozygotes exhibit an increase in pancreatic beta-cell mass pancreatic islet hyperplasia (J:80976) both male and female double homozygotes display severe islet (beta-cell) hyperplasia, with a 4.3-fold increase relative wild-type and Irs3^tm1Lhd mice, and a 1.9-fold increase relative to Irs1^tm1Jos mice notably, the mass and distribution of non-beta-cells is similar between the various groups of mice digestive/alimentary system increased pancreatic beta cell mass (J:80976) double homozygotes exhibit an increase in pancreatic beta-cell mass pancreatic islet hyperplasia (J:80976) both male and female double homozygotes display severe islet (beta-cell) hyperplasia, with a 4.3-fold increase relative wild-type and Irs3^tm1Lhd mice, and a 1.9-fold increase relative to Irs1^tm1Jos mice notably, the mass and distribution of non-beta-cells is similar between the various groups of mice liver/biliary system liver/biliary system phenotype (J:80976) double mutant livers appear normal in color; no increased fat deposition is observed

References

Original:	J:55667 Liu SC et al., "Insulin receptor substrate 3 is not essential for growth or glucose homeostasis." J Biol Chem 1999 Jun 18;274(25):18093-9
All:	4 reference(s)

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