Phenotypes associated with this allele

• Allele Symbol: Ghr^tm1Jjk
• Allele Name: targeted mutation 1, John J Kopchick
• Allele ID: MGI:2388126
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Ghr^tm1Jjk/Ghr^tm1Jjk	involves: 129P2/OlaHsd	MGI:3526390
hm2	Ghr^tm1Jjk/Ghr^tm1Jjk	involves: 129P2/OlaHsd * BALB/c	MGI:3796418
hm3	Ghr^tm1Jjk/Ghr^tm1Jjk	involves: 129P2/OlaHsd * BALB/c * C3H * C57BL/6	MGI:3807985
hm4	Ghr^tm1Jjk/Ghr^tm1Jjk	involves: 129P2/OlaHsd * BALB/c * C57BL/6	MGI:3807986
ht5	Ghr^tm1Jjk/Ghr^+	involves: 129P2/OlaHsd * BALB/c	MGI:3796427

Genotype
MGI:3526390

hm1

• Allelic Composition: Ghr^tm1Jjk/Ghr^tm1Jjk
• Genetic Background: involves: 129P2/OlaHsd

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

adipose tissue

decreased epididymal fat pad weight ( J:95149 )

• in young males (less than 2 months of age) the epididymal fat pad is reduced

growth/size/body

decreased body weight ( J:155335 )

• at 2 months, male and female mice weigh 43% and 49%, respectively, of wild-type mice weight

postnatal growth retardation ( J:95149 )

• growth retardation becomes apparent after 3 weeks of age

• growth retardation is more severe than in Ghr^tm1Mwat or Ghr^tm2Mwat homozygotes

liver/biliary system

decreased liver weight ( J:95149 )

• a disproportionate decrease in liver weight compared to body weight is seen

renal/urinary system

small kidney ( J:95149 )

• a disproportionate decrease in kidney size compared to body size is seen

nervous system

increased brain weight ( J:95149 )

• brain to body weight ratios are increased in mutants compared to wild-type mice

homeostasis/metabolism

decreased circulating insulin-like growth factor I level ( J:155335 )

increased circulating growth hormone level ( J:155335 )

Genotype
MGI:3796418

hm2

• Allelic Composition: Ghr^tm1Jjk/Ghr^tm1Jjk
• Genetic Background: involves: 129P2/OlaHsd * BALB/c

mortality/aging

extended life span ( J:63459 )

• both male and female homozygotes show a significant increase in lifespan of nearly a year relative to wild-type and heterozygous mice

perinatal lethality, incomplete penetrance ( J:44604 , J:55142 )

• perinatal or immediate postnatal mortality of newborns of homozygous breeding is higher (J:44604)

postnatal lethality, incomplete penetrance ( J:44604 )

• perinatal or immediate postnatal mortality of newborns of homozygous breeding is higher

growth/size/body

decreased birth weight ( J:55142 )

• at birth, average body weight of live pups is significantly lower in homozygous mutant females than in wild-type females (despite pregnancy prolongation)

decreased lean body mass ( J:105686 )

♂ • at 3.5 months of age, the ratio between nonbone lean mass and crown-rump length in mutant males is reduced by 43% relative to control males

abnormal body weight ( J:63459 )

• surprisingly, homozygotes reach their maximum weight at an earlier age than wild-type or heterozygous control mice

• male homozygotes reach their maximum weight at an average age of 14 weeks, whereas wild-type males reach their maximum weight 28 weeks later

• female homozygotes reach their maximum weight at an average age of 34 weeks, whereas wild-type females reach their maximum weight 12 weeks later

obese ( J:105686 )

♂ • at 3.5 months of age, male homozygotes are obese

decreased body size ( J:44604 , J:63459 )

• at 3 weeks after birth, but not at birth, homozygotes are smaller than wild-type (J:44604)

• homozygotes are significantly smaller than wild-type and heterozygous control mice, even at 1.5 yr of age (J:63459)

decreased body weight ( J:53777 , J:63459 , J:105686 , J:105921 , J:110613 , J:132437 )

• at 4 weeks of age, homozygotes weigh ~45% less than wild-type controls (J:63459)

• homozygotes attain a final weight that is ~40% that of wild-type mice (J:63459)

• body weights are 46% of controls (J:132437)

♀ • at 3-5 months of age, the weight of female homozygotes is ~50% of wild-type females (J:110613)

♂ • at 12-13 weeks of age, male homozygotes weigh >50% less than wild-type males (J:53777)

♂ • at 3.5 months of age, the body weight of male homozygotes is ~50% of control males (J:105686)

decreased body length ( J:44604 , J:60207 , J:105686 )

• at 8 weeks of age, body length is shorter (J:44604)

♂ • at 3 months of age, the length of crown-rump in mutant males is decreased relative to wild-type males (J:60207)

♂ • at 3.5 months of age, the body length of male homozygotes is ~74% that of control males (J:105686)

♂ • at 3.5 months of age, the ratio between nonbone lean mass and crown-rump length in mutant males is reduced by 43% relative to control males (J:105686)

proportional dwarf ( J:44604 )

• proportionate dwarfism

postnatal growth retardation ( J:44604 , J:63459 )

• severe (J:44604)

• after weaning, both male and female homozygotes display significantly slower rates of growth relative to wild-type and heterozygous controls (J:63459)

• notably, the gender difference observed between male and female control mice is lost in homozygotes (J:63459)

decreased fetal size ( J:55142 )

• at days 17 and 18 of gestation, fetuses of female mutants are significantly smaller than fetuses of wild-type females

• at day 17 of gestation, the crown-rump length of fetuses in female homozygous mutants is significantly reduced relative to wild-type females

decreased fetal weight ( J:55142 )

• at day 17 of gestation, the weight of fetuses in female homozygous mutants is significantly reduced relative to wild-type females

• comparisons of matings between homozygous mutant females and wild-type or homozygous mutant males indicate that the alteration of fetal weight is related to maternal rather than fetal genotype

fetal growth retardation ( J:55142 )

• significantly lower rate of fetal growth between days 16 and 17 of gestation, with a modest but significant reduction in fetal weight of female mutants at day 14

homeostasis/metabolism

decreased triiodothyronine level ( J:60207 )

♂ • at 3 months of age, male homozygotes show reduced free T3 levels relative to wild-type males (5.61 pmol/l vs 6.32 pmol/l, respectively)

decreased circulating glucose level ( J:105686 , J:110613 )

♀ • at 3-5 months of age, female homozygotes display a significant reduction in fasting glucose plasma concentrations (58% of wild-type values) (J:110613)

♂ • at 3.5 months of age, male homozygotes display a 23% reduction in serum levels of nonfasting glucose relative to control males (J:105686)

decreased circulating testosterone level ( J:53777 , J:105921 )

♂ • in response to GnRH treatment, male homozygotes show a significantly attenuated increase in circulating testosterone levels relative to similarly-treated control mice (J:53777)

♂ • notably, basal plasma testosterone levels in untreated control and mutant males are similar (J:53777)

♂ • at day 36, immature male homozygots show an attenuated testosterone response to luteinizing hormone treatment relative to wild-type males (J:105921)

decreased circulating estradiol level ( J:79216 )

♀ • at 3-6 months of age, serum estradiol levels in female homozygotes are reduced to ~33% of control levels

decreased circulating luteinizing hormone level ( J:53777 )

♂ • in response to GnRH treatment, male homozygotes show a significantly attenuated increase in plasma LH levels relative to similarly-treated control mice (3.7-fold vs 15.5-fold increase, respectively)

♂ • notably, basal plasma LH levels in untreated control and mutant males are similar

increased circulating prolactin level ( J:53777 )

♂ • at 12-13 weeks of age, circulating PRL concentrations are significantly elevated in homozygous mutant males relative to control siblings

decreased circulating insulin level ( J:105686 , J:110613 )

♀ • at 3-5 months of age, female homozygotes display a drastic reduction in fasting insulin plasma concentrations relative to wild-type (less than 4 uIU/ml, i.e. below detection limit) (J:110613)

♂ • at 3.5 months of age, male homozygotes display a 75% reduction in serum levels of nonfasting insulin relative to control males (J:105686)

decreased circulating insulin-like growth factor I level ( J:44604 , J:53777 , J:60207 , J:63459 )

• 90% decrease in serum insulin-like growth factor (J:44604)

• at 23 months of age, IGF-I levels of homozygous mutants remain at less than 10% of the levels found in wild-type controls, with no significant changes between genders or with age (J:63459)

• in addition, at 60 days, both male and female homozygotes show a 20-fold reduction in IGFBP-3 levels relative to wild-type controls (J:63459)

♂ • at 12-13 weeks of age, plasma IGF-I levels are undetectable in male homozygotes (J:53777)

♂ • at 3 months of age, male homozygotes show reduced IGF-I levels relative to wild-type males (27.8 ng/ml vs 384 ng/ml, respectively), along with reduced levels of IGF-I mRNA in liver (16.8% of wild-type) (J:60207)

increased circulating leptin level ( J:105686 )

♂ • at 3.5 months of age, serum leptin levels are increased 4.8-fold in mutant males relative to control males

increased circulating growth hormone level ( J:44604 )

• elevation in serum growth hormone concentrations

abnormal circulating lipid level ( J:105686 )

♂ • at 3.5 months of age, male homozygotes show a 71% reduction in serum apoB levels relative to control males

increased circulating corticosterone level ( J:105686 )

♂ • at 3.5 months of age, male homozygotes display a 115% increase in serum levels of nonfasting corticosterone relative to control males

decreased circulating cholesterol level ( J:105686 )

♂ • at 3.5 months of age, male homozygotes show a 40% reduction in total serum cholesterol levels relative to control males

decreased circulating HDL cholesterol level ( J:105686 )

♂ • at 3.5 months of age, male homozygotes show a 40% reduction in serum HDL levels relative to control males

decreased circulating LDL cholesterol level ( J:105686 )

♂ • at 3.5 months of age, male homozygotes show a 61% reduction in serum LDL levels relative to control males

decreased circulating VLDL cholesterol level ( J:105686 )

♂ • at 3.5 months of age, male homozygotes show a 37% reduction in serum VLDL levels relative to control males

decreased circulating triglyceride level ( J:105686 )

♂ • at 3.5 months of age, male homozygotes show a 47% reduction in serum triglyceride levels relative to control males

increased insulin sensitivity ( J:110613 )

♀ • at 3-5 months of age, increased insulin sensitivity in female homozygotes is partly attributed to compensatory changes of insulin signal transduction in the liver, including increased insulin receptor (IR) abundance, increased insulin-stimulated IR tyrosine phosphorylation, normal efficiency of IRS-1 and Shc tyrosine phosphorylation, and normal activation of PI 3-kinase by insulin

increased circulating adiponectin level ( J:132437 )

• increase in serum adiponectin levels at 5 months of age

• however, no differences in serum leptin levels

reproductive system

decreased prostate gland ventral lobe weight ( J:53777 )

♂ • at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute ventral prostate weight (60% of wild-type)

abnormal seminal vesicle weight ( J:105921 )

♂ • male homozygotes display a significant increase in seminal vesicle weight at a later age than wild-type males i.e. after 35 days versus between 30 and 35 days of age, respectively

decreased seminal vesicle weight ( J:53777 , J:105921 )

♂ • at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute seminal vesicle weight (49% of wild-type) (J:53777)

♂ • absolute weights of mutant seminal vesicles (both emptied and weighed with their secretions) are significantly reduced at all ages examined after day 30 (J:105921)

decreased corpora lutea number ( J:79216 )

♀ • at 3-6 months of age, the mean number of corpora lutea (CL) per mouse at estrus is reduced to 42.5% of CL number in control females

♀ • at day 7 of gestation (early pregnancy), female homozygotes show a significant reduction in the mean number of active CL (52% of wild-type number), with no significant changes in serum progesterone concentrations

decreased mature ovarian follicle number ( J:79216 )

♀ • at 3-6 months of age, the mean number of preovulatory follicles (PF) per mouse at estrus is reduced to 67% of PF number in control females

♀ • reduction in PF number at estrus is not due to atresia of antral follicles, since number of apoptotic antral follicles in mutant females is decreased to 11.5% of wild-type number

impaired ovarian folliculogenesis ( J:79216 )

♀ • reduction in estradiol levels and ovulation rate may reflect a quantitative deficit in earlier follicle development

decreased testis weight ( J:53777 , J:60207 , J:105921 )

♂ • at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute testicular weight (53% of wild-type) (J:53777)

♂ • at 3 months, mutant testicular weight is proportionately decreased as shown by the testis weight/BW ratio (% of wild-type) (J:60207)

♂ • average testicular weights of male homozygotes are reduced relative to wild-type at all ages examined between 25 days and 60 days of age (J:105921)

abnormal ovary physiology ( J:79216 )

♀ • adult ovarian dysfunction is associated with a 37% reduction in ovarian IGF-I mRNA expression, while expression of key steroidogenic enzyme mRNAs remains normal

abnormal testes secretion ( J:105921 )

♂ • at 60 days of age (but not prior), intratesticular testosterone concentrations are significantly lower in mutant males relative to wild-type males

♂ • total testosterone content of mutant testes is significantly reduced at 50 and at 60 days of age

♂ • unlike wild-type males, mutant males fail to show significant age-related changes in the content of testosterone in the testes

decreased testes secretion ( J:53777 )

♂ • in vitro, both basal and LH-stimulated testosterone release from isolated testes of mutant males are decreased relative to control testes

♂ • in vitro, total testosterone production in response to LH treatment is also decreased in isolated mutant testes

increased uterus weight ( J:55142 )

♀ • at the first vaginal estrus, uterine weight is 2.5- to 3-fold higher in rhIGF-I-treated female mutants than in saline-treated female mutants, although body weight remains unaffected

abnormal spermatogenesis ( J:105921 )

♂ • male homozygotes show delayed appearance of advanced germ cells within testes

abnormal spermatid morphology ( J:105921 )

♂ • unlike wild-type males, most male homozygotes show absence of elongated spermatids in the testes before the age of 40 days

abnormal epididymis weight ( J:105921 )

♂ • male homozygotes display an increase in epididymis weight at a later age than wild-type males i.e. between 40 and 60 days versus between 35 and 60 days of age, respectively

decreased epididymis weight ( J:105921 )

♂ • average weights of mutant epididymes are significantly reduced at all ages examined between 25 days and 60 days of age

delayed female fertility ( J:44604 )

♀ • average age of first pregnancy in females is delayed

delayed male fertility ( J:79216 )

♂ • male homozygotes fail to successfully impregnate control females until roughly 9 weeks of age; one mutant male failed to impregnate either of the females with whom he was caged for >90 days

♂ • delayed attainment of fertility in males, but not females, is likely to contribute to the delayed age at first conception

delayed sexual maturation ( J:55142 , J:79216 , J:105921 )

♀ • sexual maturation is significantly delayed in homozygous mutant females relative to wild-type females (J:55142)

♀ • when young female mutants are mated to control males, latency to first mating and age of the female at first mating are significantly delayed; however, maternal age at first conception is similar between groups (~6 weeks) (J:79216)

♂ • males homozygotes display a significant delay in the onset of puberty as shown by changes in testicular function, SV weight, germ cell formation, and timing of preputial separation (J:105921)

delayed vaginal opening ( J:55142 )

♀ • the age of vaginal opening is significantly delayed in homozygous mutant females relative to wild-type females, but it can be advanced by treatment with recombinant human (rh)IGF-I

♀ • delay of vaginal opening in mutant versus wild-type females is nearly identical in the two groups of animals receiving either saline or rhIGF-I treatment (7.1 and 7.4 days, respectively)

♀ • rhIGF-I treatment accelerates vaginal opening by ~3 days in mutant females and by ~2 days in wild-type females

♀ • the interval between the day of vaginal opening and the day of first vaginal estrus is significantly longer in rhIGF-I-treated female mutants than in saline-treated female mutants

delayed balanopreputial separation ( J:105921 )

♂ • in male homozygotes, balanopreputial separation is delayed by ~5 days relative to wild-type males

long gestation period ( J:55142 )

♀ • length of pregnancy is significantly greater in homozygous mutant versus wild-type females (20 days vs 19 days, respectively)

decreased ovulation rate ( J:79216 )

♀ • a major decrease in ovulation rate is the primary maternal variable associated with reduced litter size; possibly related to reduced ovarian IGF-I mRNA expression

prolonged diestrus ( J:79216 )

♀ • longer estrous cycles in group housed females are associated with extended periods of diestrus

abnormal metestrus ( J:79216 )

♀ • longer estrous cycles in group housed females are associated with atypical cellular associations in the late metestrus/diestrus transition

prolonged estrous cycle ( J:79216 )

♀ • at 3-6 months of age, mean estrus cycle duration (ECD) is prolonged and more variable in group housed than in individually housed female homozygotes

♀ • ECD is more significantly increased by group housing in mutant than in wild-type females, suggesting altered sensitivity to female pheromonal signals in mutant females

♀ • longer ECD in group housed females is associated with prolonged periods of diestrus and atypical cellular associations in the late metestrus/diestrus transition

♀ • notably, individually housed female homozygotes show no significant differences in ECD relative to control females (~5 days)

impaired luteinization ( J:79216 )

♀ • significantly less virgin mutant females display pseudopregnancies when initially placed with vasectomized sterile males than wild-type female counterparts

♀ • however, with time and repeated mating, mutant females are able to normalize their luteal response to sterile mating and display pseudopregnancies of comparable duration and frequency to that of wild-type controls

impaired embryo implantation ( J:79216 )

♀ • at day 7 of gestation (early pregnancy), female homozygotes show a significant reduction in the mean number of uterine implantation sites (55% of wil-type number)

female infertility ( J:79216 )

♀ • although most female homozygotes are fertile, a subset appear infertile, failing to conceive when mated multiple times with males of proven fertility

decreased litter size ( J:44604 , J:79216 )

♀ • litter size of female homozygotes mated to male homozygotes is reduced to ~40% of litter size in heterozygous x heterozygous and wild-type x wild-type matings (J:44604)

reduced male fertility ( J:53777 )

♂ • only 14 of 19 male homozygotes are fertile, possibly due to hyperprolactinemia

♂ • only 53% of control females housed with homozygous mutant males became pregnant vs 88% of control females housed with control males

♂ • however, litter size and mean number of pups found dead does not differ between litters sired by control and homozygous mutant males

embryo

increased placenta weight ( J:55142 )

♀ • surprisingly, at days 16, 17 and 18 of gestation, placental weight is significantly higher in pregnant female mutants than in wild-type females

♀ • alteration of placental weight is related to maternal rather than fetal genotype

endocrine/exocrine glands

decreased pituitary gland weight ( J:53777 )

♂ • at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute pituitary weight (53% of wild-type)

decreased prostate gland ventral lobe weight ( J:53777 )

♂ • at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute ventral prostate weight (60% of wild-type)

abnormal seminal vesicle weight ( J:105921 )

♂ • male homozygotes display a significant increase in seminal vesicle weight at a later age than wild-type males i.e. after 35 days versus between 30 and 35 days of age, respectively

decreased seminal vesicle weight ( J:53777 , J:105921 )

♂ • at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute seminal vesicle weight (49% of wild-type) (J:53777)

♂ • absolute weights of mutant seminal vesicles (both emptied and weighed with their secretions) are significantly reduced at all ages examined after day 30 (J:105921)

decreased corpora lutea number ( J:79216 )

♀ • at 3-6 months of age, the mean number of corpora lutea (CL) per mouse at estrus is reduced to 42.5% of CL number in control females

♀ • at day 7 of gestation (early pregnancy), female homozygotes show a significant reduction in the mean number of active CL (52% of wild-type number), with no significant changes in serum progesterone concentrations

decreased mature ovarian follicle number ( J:79216 )

♀ • at 3-6 months of age, the mean number of preovulatory follicles (PF) per mouse at estrus is reduced to 67% of PF number in control females

♀ • reduction in PF number at estrus is not due to atresia of antral follicles, since number of apoptotic antral follicles in mutant females is decreased to 11.5% of wild-type number

impaired ovarian folliculogenesis ( J:79216 )

♀ • reduction in estradiol levels and ovulation rate may reflect a quantitative deficit in earlier follicle development

decreased testis weight ( J:53777 , J:60207 , J:105921 )

♂ • at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute testicular weight (53% of wild-type) (J:53777)

♂ • at 3 months, mutant testicular weight is proportionately decreased as shown by the testis weight/BW ratio (% of wild-type) (J:60207)

♂ • average testicular weights of male homozygotes are reduced relative to wild-type at all ages examined between 25 days and 60 days of age (J:105921)

abnormal ovary physiology ( J:79216 )

♀ • adult ovarian dysfunction is associated with a 37% reduction in ovarian IGF-I mRNA expression, while expression of key steroidogenic enzyme mRNAs remains normal

abnormal testes secretion ( J:105921 )

♂ • at 60 days of age (but not prior), intratesticular testosterone concentrations are significantly lower in mutant males relative to wild-type males

♂ • total testosterone content of mutant testes is significantly reduced at 50 and at 60 days of age

♂ • unlike wild-type males, mutant males fail to show significant age-related changes in the content of testosterone in the testes

decreased testes secretion ( J:53777 )

♂ • in vitro, both basal and LH-stimulated testosterone release from isolated testes of mutant males are decreased relative to control testes

♂ • in vitro, total testosterone production in response to LH treatment is also decreased in isolated mutant testes

nervous system

decreased pituitary gland weight ( J:53777 )

♂ • at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute pituitary weight (53% of wild-type)

decreased brain weight ( J:132437 )

• brain weight is decreased even after normalizing for differences in body size

increased brain weight ( J:60207 , J:105686 )

• at 3 months, mutant brain weight is Disproportionately increased as shown by the brain weight/BW ratio (% of wild-type) (J:60207)

♂ • at 3.5 months of age, brain weight relative to total body weight is disproportionally larger (~164%) in mutant males versus control males (J:105686)

limbs/digits/tail

short femur ( J:60207 )

♂ • at 3 months of age, the length of femur in mutant males is decreased relative to wild-type males

short tibia ( J:60207 )

♂ • at 3 months of age, the length of tibia in mutant males is decreased relative to wild-type males

skeleton

decreased length of long bones ( J:60207 )

♂ • at 3 months of age, male homozygotes display reduced longitudinal bone growth relative to wild-type males

short femur ( J:60207 )

♂ • at 3 months of age, the length of femur in mutant males is decreased relative to wild-type males

short tibia ( J:60207 )

♂ • at 3 months of age, the length of tibia in mutant males is decreased relative to wild-type males

decreased bone mineral content ( J:60207 , J:105686 )

• at 3 months of age, male homozygotes display a significantly reduced bone mineral content (BMC) in total body as well as in spine, femur, tibia, and cranium (J:60207)

• in addition, BMC/body weight is reduced for total body (-32%), spine (-34%), and femur (-26%) (J:60207)

♂ • at 3.5 months of age, the ratio between total bone mineral content to crown-rump length and total bone area to crown-rump length is reduced by 45% and 23%, respectively, in mutant versus control males (J:105686)

decreased areal bone mineral density ( J:60207 )

• area bone mineral density (BMD) is reduced in total body (-11%), spine (-20%), femur (-32%), tibia (-29%), and cranium (-29%)

• notably, trabecular volumetric BMD is not significantly altered in the metaphysis of the distal femur and the proximal tibia

abnormal compact bone morphology ( J:60207 )

♂ • at 3 months of age, male homozygotes display decreased cortical BMC caused by a reduction in radial cortical growth of the long bones

abnormal skeleton development ( J:60207 )

♂ • at 3 months of age, male homozygotes display disproportional skeletal growth, as shown by decreased femur/crown-rump and femur/tibia ratios relative to wild-type mice

abnormal long bone epiphyseal plate morphology ( J:60207 )

♂ • at 3 months of age, male homozygotes display decreased width of the distal growth plate in the femur

♂ • in constrast to the femur, the epiphysis of the mutant proximal tibia is unexpectedly chondrogenic

abnormal bone ossification ( J:60207 )

♂ • at 3 months, the proximal tibial epiphysis of mutant males is chondrogenic rather than filled with trabecular bone

cardiovascular system

abnormal artery morphology ( J:157146 )

• lumen diameter of arteries is reduced compared to controls

• however, no differences in wall thickness or wall cross-sectional area of mesenteric arteries across the pressure range of 3-180 mm Hg

decreased heart weight ( J:60207 , J:157146 )

• at 3 months, mutant heart weight is proportionately decreased as shown by the heart weight/BW ratio (% of wild-type) (J:60207)

• mean heart weight is reduced in mutants, however the heart weight to body weight ratio is not different (J:157146)

decreased systemic arterial systolic blood pressure ( J:157146 )

• mean systolic blood pressure is lower compared to controls

hematopoietic system

decreased spleen weight ( J:60207 )

• at 3 months, mutant spleen weight is proportionately decreased as shown by the spleen weight/BW ratio (% of wild-type)

immune system

decreased spleen weight ( J:60207 )

• at 3 months, mutant spleen weight is proportionately decreased as shown by the spleen weight/BW ratio (% of wild-type)

decreased susceptibility to autoimmune diabetes ( J:59132 )

• at 10 weeks after induction of diabetes with streptozotocin, female homozygotes develop levels of hyperglycemia that are equivalent to those observed in STZ-treated wild-type and heterozygous control mice; however, STZ-treated mutant females fail to show evidence of glomerulosclerosis, increases in glomerular volume or increases in the ratio of mesangial area to total glomerular area, indicating protection against diabetes-induced nephropathy

liver/biliary system

decreased liver weight ( J:60207 , J:105686 )

• at 3 months, mutant liver weight is disproportionately decreased as shown by the liver weight/BW ratio (% of wild-type) (J:60207)

♂ • at 3.5 months of age, liver weight relative to total body weight is disproportionally smaller (~76%) in mutant males versus control males (J:105686)

renal/urinary system

decreased kidney weight ( J:60207 , J:132437 )

• at 3 months, mutant kidney weight is proportionately decreased as shown by the kidney weight/BW ratio (% of wild-type) (J:60207)

behavior/neurological

abnormal learning/memory/conditioning ( J:96518 )

• unexpectedly, middle-aged and old homozygotes display superior memory performance in the inhibitory avoidance test relative to age-matched wild-type littermates, indicating that their age-induced decline in memory retention is delayed

abnormal avoidance learning behavior ( J:96518 )

• in the inhibitory avoidance learning task (a measure of cognitive aging), learning and memory retention in old homozygotes (24-30 months of age) does not decline between the 24-hr, 7-day and 28-day retention tests and is not significantly different from that in young homozygotes (2-4 months of age)

• differences in retention are not attributed to altered locomotor behavior or emotionality, as between the ages of 17 and 20 months wild-type and mutant mice do not differ in number of open or closed arms entered, time spent in closed or open arms or time taken to first enter an open arm in the elevated-plus maze test

abnormal food intake ( J:105686 )

♂ • following intracerebroventricular (ICV) ghrelin injection, both fasted and fed male homozygotes show a blunted feeding response relative to similarly-treated control males

♂ • ICV injection of ghrelin generated a similar increase in total serum gherlin levels in mutant and control males (4.9- and 6.4-fold, respectively); however, ghrelin had no acute effect on serum leptin or corticosterone levels in either group of mice

increased food intake ( J:105686 )

♂ • fasted male homozygotes show a significantly higher food consumption per gram body weight than control males

adipose tissue

increased white adipose tissue amount ( J:132437 )

• increase in subcutaneous mass when fat mass to body weight is normalized

increased retroperitoneal fat pad weight ( J:105686 , J:132437 )

• increase in retroperitoneal fat pad mass when fat mass to body weight is normalized (J:132437)

♂ • at 3.5 months of age, retroperitoneal adipose tissue weight relative to total body weight is disproportionally larger (~227%) in mutant males versus control males (J:105686)

increased interscapular fat pad weight ( J:105686 )

• at 3.5 months of age, interscapular brown adipose tissue weight relative to total body weight is disproportionally larger (~176%) in mutant males versus control males

increased percent body fat/body weight ( J:105686 , J:132437 )

♂ • at 3.5 months of age, the percent body fat is increased 2.4-fold in mutant males relative to control males (J:105686)

cellular

abnormal spermatid morphology ( J:105921 )

♂ • unlike wild-type males, most male homozygotes show absence of elongated spermatids in the testes before the age of 40 days

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Laron syndrome		DOID:9521	OMIM:262500	J:44604 , J:157146

Genotype
MGI:3807985

hm3

• Allelic Composition: Ghr^tm1Jjk/Ghr^tm1Jjk
• Genetic Background: involves: 129P2/OlaHsd * BALB/c * C3H * C57BL/6

endocrine/exocrine glands

decreased activity of thyroid gland ( J:103286 )

• at 4-5 months of age, female homozygotes are only mildly hypothyroid relative to control littermates

homeostasis/metabolism

decreased circulating thyroxine level ( J:103286 )

• at 4-5 months of age, plasma levels of T4 in female mutants are approximately one-third lower than in control females; however, the ratio of T3-to-T4 is similar to controls

decreased circulating triiodothyronine level ( J:103286 )

• at 4-5 months of age, plasma levels of T3 in female mutants are approximately one-third lower than in control females; however, the ratio of T3-to-T4 is similar to controls

decreased circulating glucose level ( J:103286 )

• at 4-5 months of age, plasma glucose levels in ad libitum-fed homozygotes (male and females) are lower than in control mice in measurements taken in both morning and afternoon; however, these reductions are sex-dependent

• plasma glucose levels in fed young adult homozygotes sacrificed in the morning are significantly reduced in males, but are nonsignificantly lower in female homozygotes relative to control mice

• although morning plasma glucose levels are normal in fed female homozygotes, they drop significantly in the afternoon, suggesting a different diurnal pattern of glucose regulation in females than males

increased circulating corticosterone level ( J:103286 )

• at 4-5 months of age, basal (unstressed) plasma corticosterone levels in female homozygotes are similar to those in control females, while mutant males display significantly elevated levels over control males in the afternoon only

• following repeated anesthesia and exposure to a novel cage, corticosterone levels in stressed female homozygotes are similar to those in stressed control females

decreased circulating insulin level ( J:103286 )

• plasma insulin levels in male homozygotes fail to reach the limit of detection (4 uIU/ml) for the RIA assay used, while female homozygotes show a ~66% reduction relative to control females

decreased body temperature ( J:103286 )

• over a 24-hr period, the average body core temperature in female homozygotes (4-5 months of age) is 0.4C lower than that of control females

• however, these differences are significant only during two 1-hr periods at 1 and 4 hr before lights off and the 3 hr prior to lights on

Genotype
MGI:3807986

hm4

• Allelic Composition: Ghr^tm1Jjk/Ghr^tm1Jjk
• Genetic Background: involves: 129P2/OlaHsd * BALB/c * C57BL/6

growth/size/body

decreased body weight ( J:107763 )

• as early as 3 days of age, mutant pups are already retarded by 15% in mean body weight, although serum insulin and glucose concentrations remain normal

• by 10 days of age, mutant pups display a 22% reduction in mean body weight, and blood glucose and serum insulin levels are reduced to a similar extent as found in adult mutant dwarfs

postnatal growth retardation ( J:107763 )

• at 2 months of age, homozygotes show a 51% reduction in growth relative to wild-type mice, as reflected by body weight

homeostasis/metabolism

abnormal blood homeostasis ( J:107763 )

• at 3-4 months of age, normally fed homozygotes show significantly increased serum levels of urea and alanine aminotransferase relative to wild-type

• however, at 4 months of age, serum cholesterol, triglyceride, and HDL cholesterol levels remain normal

decreased circulating glucose level ( J:107763 )

• at 2 months of age, homozygotes display 80% of wild-type blood glucose levels under random-fed status

• when fasted for 24 hrs, the reduction in blood glucose levels seen in mutants remains significant

hypoglycemia ( J:107763 )

• at 7 months of age and under random-fed status, homozygotes are hypoglycemic relative to wild-type mice

decreased circulating glucagon level ( J:107763 )

• at 2 months of age, homozygotes display 78% of wild-type serum glucagon levels

decreased circulating insulin level ( J:107763 )

• at 2 months of age, homozygotes display only 40% of wild-type serum insulin levels under random-fed status

• as expected, insulin mRNA levels in the mutant pancreas are reduced to 40% relative to wild-type levels

decreased circulating insulin-like growth factor I level ( J:107763 )

• at 2-3 months of age, pancreatic IGF-I mRNA levels are reduced to 38% of wild-type levels

• in addition, liver IGF-I mRNA levels, which show a 0.7-kb major form and a 7-kb minor form, are reduced to 37% and 24% of wild-type levels, respectively

increased circulating creatine kinase level ( J:107763 )

• at 3-4 months of age, normally fed homozygotes show significantly increased serum levels of creatine kinase relative to wild-type

increased circulating serum albumin level ( J:107763 )

• at 3-4 months of age, normally fed homozygotes show significantly increased serum levels of albumin relative to wild-type

increased insulin sensitivity ( J:107763 )

• insulin tolerance tests performed in 7-mo-old homozygotes of both sexes in the random fed state indicate a further reduction in blood glucose levels of 60% and 67% at 40 and 60 min relative to wild-type levels

increased circulating chloride level ( J:107763 )

• at 3-4 months of age, normally fed homozygotes show significantly increased serum levels of chloride relative to wild-type

endocrine/exocrine glands

decreased pancreatic beta cell mass ( J:107763 )

• at 2 months of age, total beta-cell mass is reduced 4.5-fold in mutant mice, significantly more than their body size reduction

• reduction in pancreatic islet mass appears to be related to decreases in proliferation and cell growth

• notably, total alpha-cell mass (in mg) remains unaffected

small pancreatic islets ( J:107763 )

• at 2 months of age, the average size of mutant pancreatic islets is only one-third of that in wild-type mice

• as early as 10 days of age, mutant pups show a 28% reduction in pancreatic islet size relative wild-type pups

liver/biliary system

decreased liver weight ( J:107763 )

• at 4 months of age, homozygotes show a 22% reduction in relative liver weight to total body weight; no sexual dimorphism is observed

adipose tissue

increased abdominal fat pad weight ( J:107763 )

• at 4 months of age, the relative weight of subcutaneous, lateral abdominal fat increases 2.5-fold in mutants relative to wild-type littermates

• other visceral fat pads in the abdomen and surrounding the kidney remain unaffected

Genotype
MGI:3796427

ht5

• Allelic Composition: Ghr^tm1Jjk/Ghr⁺
• Genetic Background: involves: 129P2/OlaHsd * BALB/c

growth/size/body

decreased body length ( J:44604 )

• females, but not males, are shorter than wild-type females

postnatal growth retardation ( J:44604 )

• growth of females, but not males, is mildly but significantly retarded compared with wild-type