Mouse Genome Informatics
hm
    Ghrtm1Jjk/Ghrtm1Jjk
involves: 129P2/OlaHsd * BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• both male and female homozygotes show a significant increase in lifespan of nearly a year relative to wild-type and heterozygous mice
• perinatal or immediate postnatal mortality of newborns of homozygous breeding is higher (J:44604)
• perinatal or immediate postnatal mortality of newborns of homozygous breeding is higher

growth/size
• at 3.5 months of age, the percent body fat is increased 2.4-fold in mutant males relative to control males (J:105686)
• at birth, average body weight of live pups is significantly lower in homozygous mutant females than in wild-type females (despite pregnancy prolongation)
• 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)
• 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
• at 3.5 months of age, male homozygotes are obese (J:105686)
• 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)
• at 12-13 weeks of age, male homozygotes weigh >50% less than wild-type males (J:53777)
• 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 3.5 months of age, the body weight of male homozygotes is ~50% of control males (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)
• proportionate dwarfism
• 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)
• 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
• 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
• 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
• 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)
• 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)
• at 3-6 months of age, serum estradiol levels in female homozygotes are reduced to ~33% of control levels
• 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
• at 12-13 weeks of age, circulating PRL concentrations are significantly elevated in homozygous mutant males relative to control siblings
• 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)
• 90% decrease in serum insulin-like growth factor (J:44604)
• 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)
• 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 3.5 months of age, serum leptin levels are increased 4.8-fold in mutant males relative to control males (J:105686)
• elevation in serum growth hormone concentrations
• at 3.5 months of age, male homozygotes show a 71% reduction in serum apoB levels relative to control males (J:105686)
• at 3.5 months of age, male homozygotes display a 115% increase in serum levels of nonfasting corticosterone relative to control males (J:105686)
• at 3.5 months of age, male homozygotes show a 40% reduction in total serum cholesterol levels relative to control males (J:105686)
• at 3.5 months of age, male homozygotes show a 40% reduction in serum HDL levels relative to control males (J:105686)
• at 3.5 months of age, male homozygotes show a 61% reduction in serum LDL levels relative to control males (J:105686)
• at 3.5 months of age, male homozygotes show a 37% reduction in serum VLDL levels relative to control males (J:105686)
• at 3.5 months of age, male homozygotes show a 47% reduction in serum triglyceride levels relative to control males (J:105686)
• 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 (J:110613)
• increase in serum adiponectin levels at 5 months of age
• however, no differences in serum leptin levels
• 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)

reproductive system
• 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 (J:79216)
• 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 (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 (J:79216)
• 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 (J:79216)
• reduction in estradiol levels and ovulation rate may reflect a quantitative deficit in earlier follicle development (J:79216)
• at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute ventral prostate weight (60% of wild-type) (J:53777)
• 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 (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)
• 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)
• adult ovarian dysfunction is associated with a 37% reduction in ovarian IGF-I mRNA expression, while expression of key steroidogenic enzyme mRNAs remains normal (J:79216)
• in vitro, both basal and LH-stimulated testosterone release from isolated testes of mutant males are decreased relative to control testes (J:53777)
• in vitro, total testosterone production in response to LH treatment is also decreased in isolated mutant testes (J:53777)
• at 60 days of age (but not prior), intratesticular testosterone concentrations are significantly lower in mutant males relative to wild-type males (J:105921)
• total testosterone content of mutant testes is significantly reduced at 50 and at 60 days of age (J:105921)
• unlike wild-type males, mutant males fail to show significant age-related changes in the content of testosterone in the testes (J:105921)
• 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 (J:55142)
• male homozygotes show delayed appearance of advanced germ cells within testes (J:105921)
• unlike wild-type males, most male homozygotes show absence of elongated spermatids in the testes before the age of 40 days (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 (J:105921)
• average weights of mutant epididymes are significantly reduced at all ages examined between 25 days and 60 days of age (J:105921)
• average age of first pregnancy in females is delayed
• 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)
• 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
• sexual maturation is significantly delayed in homozygous mutant females relative to wild-type females (J:55142)
• unlike prepubertal control females, mutant females fail to mate within 4 days of introduction of the male, no peak in mating activity is observed, and mean latency to first mating is delayed by ~10 days, suggesting altered pheromonal sensitivity and/or male-induced acceleration of female puberty (J:79216)
• although puberty onset is delayed in female homozygotes, the age of attainment of fertility is similar between mutant and wild-type females (J:79216)
• both puberty onset and attainment of fertility are delayed in male homozygotes (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)
• in male homozygotes, balanopreputial separation is delayed by ~5 days relative to wild-type males (J:105921)
• 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
• length of pregnancy is significantly greater in homozygous mutant versus wild-type females (20 days vs 19 days, respectively) (J:55142)
• 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 (J:79216)
• longer estrous cycles in group housed females are associated with extended periods of diestrus (J:79216)
• longer estrous cycles in group housed females are associated with atypical cellular associations in the late metestrus/diestrus transition (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 (J:79216)
• 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 (J:79216)
• longer ECD in group housed females is associated with prolonged periods of diestrus and atypical cellular associations in the late metestrus/diestrus transition (J:79216)
• notably, individually housed female homozygotes show no significant differences in ECD relative to control females (~5 days) (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) (J:79216)
• although most female homozygotes are fertile, a subset appear infertile, failing to conceive when mated multiple times with males of proven fertility (J:79216)
• significantly less virgin mutant females display pseudopregnancies when initially placed with vasectomized sterile males than wild-type female counterparts (J:79216)
• 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 (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)
• further significant reduction in litter size observed in female homozygotes mated to male homozygotes rather than wild-type males (J:55142)
• decreased litter size reflects both maternal and paternal genotype effects and is NOT associated with increased fetal mortality (J:55142)
• only 14 of 19 male homozygotes are fertile, possibly due to hyperprolactinemia (J:53777)
• only 53% of control females housed with homozygous mutant males became pregnant vs 88% of control females housed with control males (J:53777)
• however, litter size and mean number of pups found dead does not differ between litters sired by control and homozygous mutant males (J:53777)

embryogenesis
• 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
• at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute pituitary weight (53% of wild-type)
• 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 (J:79216)
• 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 (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 (J:79216)
• 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 (J:79216)
• reduction in estradiol levels and ovulation rate may reflect a quantitative deficit in earlier follicle development (J:79216)
• at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute ventral prostate weight (60% of wild-type) (J:53777)
• 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 (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)
• 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)
• adult ovarian dysfunction is associated with a 37% reduction in ovarian IGF-I mRNA expression, while expression of key steroidogenic enzyme mRNAs remains normal (J:79216)
• in vitro, both basal and LH-stimulated testosterone release from isolated testes of mutant males are decreased relative to control testes (J:53777)
• in vitro, total testosterone production in response to LH treatment is also decreased in isolated mutant testes (J:53777)
• at 60 days of age (but not prior), intratesticular testosterone concentrations are significantly lower in mutant males relative to wild-type males (J:105921)
• total testosterone content of mutant testes is significantly reduced at 50 and at 60 days of age (J:105921)
• unlike wild-type males, mutant males fail to show significant age-related changes in the content of testosterone in the testes (J:105921)

nervous system
• at 12-13 weeks of age, male homozygotes show a dramatic reduction in absolute pituitary weight (53% of wild-type)
• brain weight is decreased even after normalizing for differences in body size
• 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
• at 3 months of age, the length of femur in mutant males is decreased relative to wild-type males
• at 3 months of age, the length of tibia in mutant males is decreased relative to wild-type males

skeleton
• at 3 months of age, male homozygotes display reduced longitudinal bone growth relative to wild-type males
• at 3 months of age, the length of femur in mutant males is decreased relative to wild-type males
• at 3 months of age, the length of tibia in mutant males is decreased relative to wild-type males
• 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)
• 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
• at 3 months of age, male homozygotes display decreased cortical BMC caused by a reduction in radial cortical growth of the long bones
• 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
• 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
• at 3 months, the proximal tibial epiphysis of mutant males is chondrogenic rather than filled with trabecular bone

cardiovascular system
• 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
• 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)
• mean systolic blood pressure is lower compared to controls

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

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

behavior/neurological
• following intracerebroventricular (ICV) ghrelin injection, both fasted and fed male homozygotes show a blunted feeding response relative to similarly-treated control males (J:105686)
• 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 (J:105686)
• fasted male homozygotes show a significantly higher food consumption per gram body weight than control males (J:105686)
• 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
• 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

adipose tissue
• at 3.5 months of age, the percent body fat is increased 2.4-fold in mutant males relative to control males (J:105686)
• increase in subcutaneous mass when fat mass to body weight is normalized
• 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)
• increase in retroperitoneal fat pad mass when fat mass to body weight is normalized (J:132437)
• 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

Mouse Models of Human Disease
OMIM IDRef(s)
Laron Syndrome 262500 J:44604 , J:157146