Phenotypes associated with this allele

• Allele Symbol: Kl^kl
• Allele Name: klotho
• Allele ID: MGI:1889570
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Kl^kl/Kl^kl	either: C.Cg-Kl^kl or (involves: C3H/HeJ * C57BL/6J)	MGI:2181617
hm2	Kl^kl/Kl^kl	involves: 129S1/SvImJ * C3H/HeJ * C57BL/6J	MGI:5605084
hm3	Kl^kl/Kl^kl	involves: C3H/HeJ * C57BL/6J	MGI:3653638
hm4	Kl^kl/Kl^kl	involves: C3H/J * C57BL/6J	MGI:3653640
ht5	Kl^kl/Kl^+	involves: C3H/HeJ * C57BL/6J	MGI:3653641
cx6	Kl^kl/Kl^kl Tnfrsf11b^tm1Khs/Tnfrsf11b^+	involves: 129P2/OlaHsd * C3H * C57BL/6	MGI:3653639

Genotype
MGI:2181617

hm1

• Allelic Composition: Kl^kl/Kl^kl
• Genetic Background: either: C.Cg-Kl^kl or (involves: C3H/HeJ * C57BL/6J)

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

cellular

azoospermia ( J:44109 )

♂

mortality/aging

premature death ( J:44109 )

• average lifespan is 60.7 days with none surviving more than 100 days

premature aging ( J:44109 )

• overall phenotype resembles changes seen in human aging

growth/size/body

postnatal growth retardation ( J:44109 )

• beginning around 3-4 weeks of age

respiratory system

calcified pulmonary alveolus ( J:44109 )

• ectopic calcification of the alveolar cells

emphysema ( J:44109 )

• however, arterial blood oxygen content is similar to controls

cardiovascular system

arteriosclerosis ( J:44109 )

• progressive arteriosclerosis beginning around 4 weeks of age

calcified artery ( J:44109 )

• mid-sized muscular arteries show medial calcification and intimal thickening

• small arteries in the kidney are extensively calcified

calcified aorta ( J:44109 )

• extensive medial calcification in the aorta

abnormal blood circulation ( J:44109 )

• circulation slows beginning around 3-4 weeks of age

skeleton

kyphosis ( J:44109 )

abnormal bone structure ( J:44109 )

decreased osteoclast cell number ( J:44109 )

• reduced numbers

decreased bone mineral density ( J:44109 )

• decreased bone mineral density particularly in the mid portion of the long bones where density is reduced by about 20% compared to controls

decreased compact bone thickness ( J:44109 )

osteoporosis ( J:44109 )

• resembles human senile osteoporosis

abnormal bone ossification ( J:44109 )

behavior/neurological

short stride length ( J:44109 )

• base length corrected mean stride lengths are reduced

decreased locomotor activity ( J:44109 )

• become inactive starting around 3-4 weeks of age

• mice older than 6 weeks of age display about a 50% reduction in spontaneous activit

reproductive system

absent mature ovarian follicles ( J:44109 )

♀

ovary atrophy ( J:44109 )

♀

abnormal seminiferous tubule morphology ( J:44109 )

♂ • extremely atrophic

testicular atrophy ( J:44109 )

♂

vulva atrophy ( J:44109 )

♀ • external female genitalia are atrophic

uterus atrophy ( J:44109 )

♀

abnormal gametogenesis ( J:44109 )

• impaired maturation

azoospermia ( J:44109 )

♂

arrest of male meiosis ( J:44109 )

♂ • fail to mature beyond the pachytene stage

external male genitalia atrophy ( J:44109 )

♂ • external male genitalia are atrophic

infertility ( J:44109 )

• males and females are unable to mate

nervous system

abnormal adenohypophysis morphology ( J:44109 )

abnormal gonadotroph morphology ( J:44109 )

• luteinizing hormone and follicle stimulating hormone producing cells appear slightly atrophic

decreased somatotroph cell size ( J:44109 )

• growth hormone producing cells are smaller

decreased somatotroph secretory granule number ( J:44109 )

• the number of secretory granules in growth hormone producing cells is reduced

Purkinje cell degeneration ( J:44109 )

• however, no other signs of brain atrophy or age-related changes in the brain are detected

decreased Purkinje cell number ( J:44109 )

endocrine/exocrine glands

abnormal adenohypophysis morphology ( J:44109 )

abnormal gonadotroph morphology ( J:44109 )

• luteinizing hormone and follicle stimulating hormone producing cells appear slightly atrophic

decreased somatotroph cell size ( J:44109 )

• growth hormone producing cells are smaller

decreased somatotroph secretory granule number ( J:44109 )

• the number of secretory granules in growth hormone producing cells is reduced

thymus atrophy ( J:44109 )

• thymus is barely detectable at 6-9 weeks of age but appears normal at early development stages

absent mature ovarian follicles ( J:44109 )

♀

ovary atrophy ( J:44109 )

♀

abnormal seminiferous tubule morphology ( J:44109 )

♂ • extremely atrophic

testicular atrophy ( J:44109 )

♂

decreased insulin secretion ( J:44109 )

• decrease in pancreatic insulin level

immune system

thymus atrophy ( J:44109 )

• thymus is barely detectable at 6-9 weeks of age but appears normal at early development stages

abnormal leukocyte cell number ( J:44109 )

• ratio of lymphocytes to leukocytes is decreased in the peripheral blood, 34.5 +/- 7.6% compared to 61.3 +/- 14.1% in controls

decreased osteoclast cell number ( J:44109 )

• reduced numbers

homeostasis/metabolism

decreased insulin secretion ( J:44109 )

• decrease in pancreatic insulin level

hypoglycemia ( J:44109 )

• levels are 115.8 +/- 13.8 mg/dl compared to 231.5 +/- 22.6 mg/dl in controls

abnormal circulating mineral level ( J:44109 )

• slight increase in phosphorus level

increased circulating calcium level ( J:44109 )

• slight

calcinosis ( J:44109 )

• ectopic calcification of the arterial walls, stomach, bronchial mucosa, alveolar cells, choroid plexus, skin, testes, and cardiac muscle

adipose tissue

decreased subcutaneous adipose tissue amount ( J:44109 )

• barely detectable

muscle

calcified muscle ( J:44109 )

• calcification of the cardiac muscle

hematopoietic system

thymus atrophy ( J:44109 )

• thymus is barely detectable at 6-9 weeks of age but appears normal at early development stages

abnormal leukocyte cell number ( J:44109 )

• ratio of lymphocytes to leukocytes is decreased in the peripheral blood, 34.5 +/- 7.6% compared to 61.3 +/- 14.1% in controls

decreased osteoclast cell number ( J:44109 )

• reduced numbers

integument

decreased subcutaneous adipose tissue amount ( J:44109 )

• barely detectable

sparse hair ( J:44109 )

decreased hair follicle number ( J:44109 )

thin epidermis ( J:44109 )

abnormal skin condition ( J:44109 )

• overall atrophy resembling senile atrophoderma in humans

calcified skin ( J:44109 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
pulmonary emphysema		DOID:9675	OMIM:130700	J:44109

Genotype
MGI:5605084

hm2

• Allelic Composition: Kl^kl/Kl^kl
• Genetic Background: involves: 129S1/SvImJ * C3H/HeJ * C57BL/6J

vision/eye

abnormal retina morphology ( J:214493 )

• mice show normal outer nuclear layer length and thickness, and no photoreceptor degeneration by 7 weeks of age, however retinal protein expression is altered

increased a-wave latency ( J:214493 )

• scotopic a-waves reach peak amplitude more slowly with increasing age

increased b-wave latency ( J:214493 )

• scotopic b-waves reach peak amplitude more slowly with increasing age

• however, photopic b-wave latency is unaffected

decreased a-wave amplitude ( J:214493 )

• scotopic, rod dominant ERG responses show that the maximum a-wave amplitude is reduced approximately 26% in 7 week old dark-adapted mice

decreased b-wave amplitude ( J:214493 )

• scotopic, rod dominant ERG responses show that the maximum b-wave amplitude is reduced approximately 38% in 7 week old dark-adapted mice

• photopic cone dominant ERG responses show that the b-wave amplitude is reduced by about 39% at 7 weeks of age

Genotype
MGI:3653638

hm3

• Allelic Composition: Kl^kl/Kl^kl
• Genetic Background: involves: C3H/HeJ * C57BL/6J

mortality/aging

premature death ( J:81240 )

• treatment of mice with the antioxidant alpha-tocopherol did not increase lifespan

behavior/neurological

abnormal contextual conditioning behavior ( J:81240 )

• at 7 weeks of age, contextual freezing is similar in tests at 1 hour after training but reduced in tests at 24 hours after training

abnormal cued conditioning behavior ( J:81240 )

• at 7 weeks of age tone-induced freezing is reduced in test 1 and 24 hours after training; however, no difference in nociceptive responses are detected

• treatment of mice with the antioxidant alpha-tocopherol restores reactions in both tests to wild-type levels

impaired long-term object recognition memory ( J:81240 )

• at 7 weeks of age retention of novel object recognition is impaired in a test 24 hours after training but not in a test 1 hour after training or in either test at 6 weeks of age

• treatment of mice with the antioxidant alpha-tocopherol restores retention in the 24 hour test to wild-type levels

nervous system

abnormal nervous system physiology ( J:81240 )

• at 6 and 8 weeks of age Cu/Zn-superoxide dismutase activity in the hippocampus is increased by 58.6% and 49.3% compared to wild-type mice

cellular

oxidative stress ( J:81240 )

• age-dependent increases in accumulation of oxidative lipid and DNA damage are seen in the hippocampus and cerebral cortex

• treatment of mice with the antioxidant alpha-tocopherol reduces oxidative lipid damage and the number of TUNEL positive cells in the CA1 region of the hippocampus

skeleton

decreased osteoclast cell number ( J:80503 )

• reduced osteoclast numbers

short femur ( J:80503 )

osteopetrosis ( J:80503 )

• trabecular bone fraction in the metaphyseal region is increased about 3-fold compared to wild-type mice

growth/size/body

decreased body weight ( J:80503 )

postnatal growth retardation ( J:81240 )

• treatment of mice with the antioxidant alpha-tocopherol did not improve body weight gain

immune system

decreased B cell number ( J:80503 )

decreased osteoclast cell number ( J:80503 )

• reduced osteoclast numbers

limbs/digits/tail

short femur ( J:80503 )

hematopoietic system

decreased B cell number ( J:80503 )

decreased osteoclast cell number ( J:80503 )

• reduced osteoclast numbers

homeostasis/metabolism

decreased insulin secretion ( J:64878 )

• the pancreatic insulin content of 8 week old homozygotes is approximately 34 mg/g, much lower than the 171 mg/g in wildtype controls, but the glucagon content of the pancreas is normal

hypoglycemia ( J:64878 )

• in oral glucose tolerance tests homozygotes show hypoglycemia relative to wildtype controls at 0, 30, 60, and 120 minutes after glucose load, but post-fasting GH, TSH and ACTH levels are normal

decreased circulating insulin level ( J:64878 )

increased insulin sensitivity ( J:64878 )

• intraperitoneal insulin tolerance test using 0.05U/kg human insulin in 6 to 8 week old mice results in a rapid, sustained diminution in blood glucose from an already lower than normal starting point

• homozygotes have higher than normal expression of solute carrier family 2 member 4 in the skeletal muscle

endocrine/exocrine glands

decreased insulin secretion ( J:64878 )

• the pancreatic insulin content of 8 week old homozygotes is approximately 34 mg/g, much lower than the 171 mg/g in wildtype controls, but the glucagon content of the pancreas is normal

Genotype
MGI:3653640

hm4

• Allelic Composition: Kl^kl/Kl^kl
• Genetic Background: involves: C3H/J * C57BL/6J

limbs/digits/tail

decreased femur compact bone thickness ( J:56666 )

• reduced cortical bone thickness in the femur at 7 weeks of age

cellular

abnormal osteoblast physiology ( J:56666 )

• osteoblast cells from 5-6 day old mice, but not embryos, have lower alkaline phosphatase activity and decreased matrix nodule formation

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:102218 )

• at 6 weeks of age during a 20 hour restraint challenge the survival rate decreases progressively with 20 of 30 male mice dead by the end of the experiment, compared to 100% survival of wild-type mice

growth/size/body

decreased body length ( J:59775 )

• at 6-8 weeks of age, mean body length is 68.3 +/- 4.7 mm compared to 91.5 +/- 1.0 mm in wild-type mice

postnatal growth retardation ( J:66078 )

• after 3 weeks of age weight gain is greatly reduced

respiratory system

abnormal lung morphology ( J:59775 )

• lung volume is similar to wild-type but increased relative to body size

dilated pulmonary alveolar duct ( J:59775 )

• enlarged alveolar ducts

abnormal pulmonary alveolus morphology ( J:59775 )

• the number of alveoli contiguous with the alveolar ducts is reduced

• by 10 weeks of age normal alveolar structures are rarely seen

abnormal pulmonary interalveolar septum morphology ( J:59775 )

• by 10 weeks of age, calcified nodules are found attached to alveolar septa

emphysema ( J:59775 )

• first seen at 4 weeks of age and becomes more prominent by 10 weeks

decreased tidal volume ( J:59775 )

abnormal respiratory mechanics ( J:59775 )

• longer expiratory time and reduced tidal volume; however respiratory rate and blood oxygen and carbon dioxide partial pressures are similar to wild-type

increased lung compliance ( J:59775 )

• higher dynamic compliance at tidal breathing

cardiovascular system

arteriosclerosis ( J:102218 )

• mild to moderate Monckeberg type arteriosclerosis at 6 weeks of age but no appreciable calcification of the conduction system

abnormal heart valve morphology ( J:102218 )

calcified mitral valve annulus ( J:102218 )

• massive annular calcification at 6 weeks of age

calcified aortic valve annulus ( J:102218 )

• massive annular calcification at 6 weeks of age

abnormal cardiovascular system physiology ( J:102218 )

decreased heart rate ( J:102218 )

• after 4 hours of restraint bradyarrhythmias resulting from sinoatrial node dysfunction are seen; however, no supraventricular brady/tachyarrhythmias, atrial fibrilations, or ventricular tachyarrhythmias are seen

prolonged RR interval ( J:102218 )

• after 1 hour of restraint stress RR interval increases in contrast RR interval decreases in wild-type mice

• application of 1 mg/kg atropine and 2 mg/kg propranolol produces a greater prolongation of the RR interval

abnormal sinoatrial node conduction ( J:102218 )

• after overdrive pacing sinus node recovery time and rate-corrected sinus node recovery time are significantly longer

• isoproterenol-induced shortening and acetylcholine-induced prolongation of the spontaneous cycle length is increased compared to wild-type mice

adipose tissue

increased brown adipose tissue amount ( J:66078 )

• significant increase when normalized to body weight at 5 weeks of age

decreased white adipose tissue amount ( J:66078 )

• at 5 weeks of age, males posses no visible subcutaneous, mesenteric, retroperitoneal, or epididymal fat

decreased brown fat cell lipid droplet size ( J:66078 )

• brown adipose tissue contains smaller lipid droplets

homeostasis/metabolism

increased circulating noradrenaline level ( J:102218 )

• about a 2-fold increase in baseline levels; however levels decrease slightly during stress unlike in wild-type mice where levels increase dramatically

decreased body temperature ( J:66078 )

abnormal glucose homeostasis ( J:66078 )

hypoglycemia ( J:66078 )

• blood glucose is 76% of wild-type in 5-6 week old males fed ad libitum

decreased circulating insulin level ( J:66078 )

• 56% of wild-type in 5-6 week old males

improved glucose tolerance ( J:66078 )

• in 5-6 week old males

increased insulin sensitivity ( J:66078 )

• in 5-6 week old males

skeleton

abnormal osteoblast physiology ( J:56666 )

• osteoblast cells from 5-6 day old mice, but not embryos, have lower alkaline phosphatase activity and decreased matrix nodule formation

abnormal osteoclast morphology ( J:56666 )

• decreased osteoclast surface area per bone surface area and number of osteoclasts produced in vitro independent of the source of the osteoblast cells used in the culture

• however, in vitro bone resorption per osteoclast is similar to wild-type

abnormal bone mineral density ( J:56666 )

• bone mineral density is reduced in the mid portion (diaphysis) of the tibia and femur but increased in the distal portion (metaphysis)

decreased bone mineral density ( J:56666 )

• at 7 weeks of age, overall bone mineral density of the tibia is reduced by 12%

decreased bone mineral density of femur ( J:56666 )

• at 7 weeks of age, overall bone mineral densiy of the femur is reduced by 5%

decreased compact bone thickness ( J:56666 )

• at 7 weeks of age, cortical bone thickness is reduced by about 40% in the tibia

decreased femur compact bone thickness ( J:56666 )

• reduced cortical bone thickness in the femur at 7 weeks of age

abnormal osteoblast morphology ( J:56666 )

• osteoblast surface per bone surface is reduced

decreased osteoblast cell number ( J:56666 )

• 3-fold fewer osteoblast colony forming units are found in marrow cells from 4 and 7 week old mice

abnormal trabecular bone morphology ( J:56666 )

• increased density and length of trabecular at the metaphysis of the tibia and femur

• at 7 weeks of age in the tibia, trabecular bone volume and thickness are increased by 100% and 30%, respectively

decreased bone ossification ( J:56666 )

• bone formation rate is reduced by about 80-90%

decreased bone resorption ( J:56666 )

• bone resorption rate is reduced by about 60%

endocrine/exocrine glands

abnormal pancreatic beta cell morphology ( J:66078 )

• reduction in beta cell specific staining

small pancreatic islets ( J:66078 )

• reduced islet size

liver/biliary system

decreased liver weight ( J:66078 )

• at 5 weeks of age, slight but significant decrease in liver weight when normalized to body weight; however, kidney and pancreas weights are proportional to body size

abnormal liver physiology ( J:66078 )

• apparent decrease in glycogen content

hematopoietic system

abnormal osteoclast morphology ( J:56666 )

• decreased osteoclast surface area per bone surface area and number of osteoclasts produced in vitro independent of the source of the osteoblast cells used in the culture

• however, in vitro bone resorption per osteoclast is similar to wild-type

immune system

abnormal osteoclast morphology ( J:56666 )

• decreased osteoclast surface area per bone surface area and number of osteoclasts produced in vitro independent of the source of the osteoblast cells used in the culture

• however, in vitro bone resorption per osteoclast is similar to wild-type

Genotype
MGI:3653641

ht5

• Allelic Composition: Kl^kl/Kl⁺
• Genetic Background: involves: C3H/HeJ * C57BL/6J

respiratory system

calcified pulmonary alveolus ( J:59775 )

• calcification of the alveoli is detected at 120 weeks of age

emphysema ( J:59775 )

• seen at 120 weeks of age

skeleton

kyphosis ( J:59775 )

• seen at 120 weeks of age

cardiovascular system

abnormal blood vessel physiology ( J:76383 )

• blood flow restoration and capillary growth are impaired following induced hindlimb ischemia

homeostasis/metabolism

decreased insulin secretion ( J:64878 )

• the pancreatic insulin content of 8 week old heterozygotes is approximately 118 ug/g, lower than the 171 mg/g in wildtype controls and higher than the 34 mg/g in homozygotes

hypoglycemia ( J:64878 )

• in oral glucose tolerance tests heterozygotes show hypoglycemia relative to wildtype controls, but not as severe as in homozygotes

decreased circulating insulin level ( J:64878 )

endocrine/exocrine glands

decreased insulin secretion ( J:64878 )

• the pancreatic insulin content of 8 week old heterozygotes is approximately 118 ug/g, lower than the 171 mg/g in wildtype controls and higher than the 34 mg/g in homozygotes

integument

alopecia ( J:59775 )

• hair loss is seen at 120 weeks of age

Genotype
MGI:3653639

cx6

• Allelic Composition: Kl^kl/Kl^kl; Tnfrsf11b^tm1Khs/Tnfrsf11b⁺
• Genetic Background: involves: 129P2/OlaHsd * C3H * C57BL/6

skeleton

short femur ( J:80503 )

• femur length is shorter than in mice homozygous for Kl only; however osteopetrotic changes in the bone are reduced and the number of osteoclasts is similar to wild-type

growth/size/body

decreased body weight ( J:80503 )

• similar to mice homozygous for Kl mutation only

immune system

decreased B cell number ( J:80503 )

• similar to mice homozygous for Kl mutation only

limbs/digits/tail

short femur ( J:80503 )

• femur length is shorter than in mice homozygous for Kl only; however osteopetrotic changes in the bone are reduced and the number of osteoclasts is similar to wild-type

hematopoietic system

decreased B cell number ( J:80503 )

• similar to mice homozygous for Kl mutation only