Overview

Also Known As:ages with stiffened joints

This spontaneous mutation, which causes diminished inorganic pyrophosphate in the plasma and consequently extensive ectopic mineralization of the joints, arterial vasculature, the dermal sheath of vibrissae, and multiple internal organs, provides a model for generalized arterial calcification of infancy, otitis media with effusion, and tympanosclerotic otitis.

Genetic overview

Genetic Background	Generation

Enpp1^asj

Allele Type	Gene Symbol	Gene Name
Chemically induced (ENU)	Enpp1	ectonucleotide pyrophosphatase/phosphodiesterase 1

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Research Applications

Internal/Organ Research
Endocrine Deficiency Research
Developmental Biology Research

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Details

Detailed Description

Homozygotes have a diminished ability to hydrolyze ATP into AMP and inorganic phosphate, resulting in diminished inorganic pyrophosphate in the plasma and consequently extensive ectopic mineralization, particularly in the arterial blood vessels and heart, joints, kidneys, dermal sheath of vibrissae, the blood vessels but not parenchyma of the liver, as well as in the retina. Homozygotes initially appear normal but by 2 months of age they hold their forepaws closer to the body and develop a slow hobbling gait due to joint calcification. Kingman et al. (2017) found that on a diet rich in phosphorus and low in magnesium these homozygotes show accelerated stiffening of the joints and hobbling gait, but to a lesser degree than do mice homozygous for the allelic mutation ages with stiffened joints 2 Jackson (see stock 019107). Li et al (2013) showed that the lifespan of homozygotes on this high phosphorous/low magnesium diet is significantly reduced to an average of 6.4 weeks, but with no increase in embryonic lethality when pregnant dams are fed this diet. Although initially defined as a recessive allele, heterozygotes have approximately half the normal level of ENPP1 enzymatic activity in liver, lower than normal plasma PP_i, and when fed the diet rich in phosphorus/low in magnesium there is significant mineralization of the kidney medullary tubules and arcuate and renal arteries. Homozygotes also develop a distinct pathology in the middle ears that includes a thickened stapedial artery wall, fusion of the malleus and incus, and white patch on the tympanic membrane that may be calcification and are all typical symptoms of typanosclerosis. They also have a thickened round window membrane, a significant increase in mucin-secreting goblet cells, and severe otitis media resulting in moderate to severe conductive hearing loss by 3 months, which advances with age. Homozygotes may breed, but the ability to breed and maintain a litter is curtailed by progressive physical disability. Elevated dietary magnesium is one of several treatments shown to ameliorate the phenotype (Kingman et al., 2017; Li et al, 2015; Albright et al., 2015).

Development

The ages with stiffened joints mutation was discovered in the progeny of an ENU mutagenized C57BL/6J male that had been bred with a C57BL/6J female. This mutation has been maintained on the pure C57BL/6J background by backcross-intercross using either female or male homozygotes in the backcrosses to C57BL/6J. In 2011 this strain reached generation N11.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Harris BS; Ward-Bailey PF; Yu H; Bergstrom DE; Bronson RT; Donahue LR. 2011. Ages with stiffened joints, A new mutation in Enpp1 MGI Direct Data SubmissionMGI: J:174912
Li Q; Guo H; Chou DW; Berndt A; Sundberg JP; Uitto J. 2013. Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy. Dis Model Mech 6(5):1227-35PubMed: 23798568 MGI: J:201689
Tian C; Harris BS; Johnson KR. 2016. Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis. PLoS One 11(12):e0168159PubMed: 27959908 MGI: J:251638

View All References

Genetics

Enpp1^asj

Allele Symbol: Enpp1^asj

Allele Name	ages with stiffened joints
Allele Type	Chemically induced (ENU)
Allele Synonym(s)
Gene Symbol and Name	Enpp1, ectonucleotide pyrophosphatase/phosphodiesterase 1
Gene Synonym(s)
Strain of Origin	C57BL/6J
Chromosome	10
Molecular Note	This ENU induced mutation was found to be an exon 7 T to A point mutation at position 737, predicted to change a valine to an aspartic acid.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

arterial calcification of infancy

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

otitis media

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

tympanosclerosis

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Enpp1^asj related

Internal/Organ Research
- Skeleton
Endocrine Deficiency Research
- Bone/Bone Marrow Defects
Developmental Biology Research
- Skeletal Defects

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Enpp1^asj/Enpp1^asj
C57BL/6J-Enpp1/GrsrJ

behavior/neurological phenotype

abnormal gait
- on an 'acceleration diet'rich in phosphorus and low in magnesium, mutants show accelerated stiffening of the joints and hobbling gait
- slow, hobbling gait beginning at around 2 months of age due to joint disease

abnormal resting posture
- by 2 months of age homozygotes have a stiff posture with the front legs held in toward the body

cellular phenotype

increased middle ear goblet cell number
- by 2 weeks of age homozygotes have an excess of goblet cells around the opening of the Eustachian tubes and in the Eustachian tube ducts, this is still seen at 2 months of age, and excessive mucin secretion interferes with ciliary function

craniofacial phenotype

abnormal malleus morphology

abnormal round window morphology
- the round window membrane is thicker than normal and there is overossification of the reound window ridge

abnormal snout skin morphology

incudomalleolar fusion
- fusion of the malleus and incus

growth/size/body region phenotype

abnormal snout skin morphology

hearing/vestibular/ear phenotype

abnormal auditory tube morphology
- amorphous tissue is found in the Eustachian tubes

abnormal malleus morphology

abnormal middle ear morphology
- although abnormalities are not found in the inner ear, all ears with elevated ABR thresholds have middle ear defects such as retracted tympanic membrane, effusion in the middle ear, thickened epithelium with fibrous polyps, and in older mice the excessive accumulation of discharge in the external ear canal

abnormal round window morphology
- the round window membrane is thicker than normal and there is overossification of the reound window ridge

abnormal stapedial artery morphology
- the wall of the stapedial artery is thicker than normal with excessive calcium deposition

abnormal tympanic membrane morphology
- white patch at pars tensa and retracted tempanic membrane by 6 months of age

conductive hearing loss

impaired hearing
- auditory brainstem response shows moderate to severe hearing loss by 3 months of age

increased middle ear goblet cell number
- by 2 weeks of age homozygotes have an excess of goblet cells around the opening of the Eustachian tubes and in the Eustachian tube ducts, this is still seen at 2 months of age, and excessive mucin secretion interferes with ciliary function

increased or absent threshold for auditory brainstem response
- although no indication of vestibular impairment is found, hearing is impaired with normal hearing at 3 weeks of age, 20-25 db elevations in thresholds occurs by 6 weeks of age, a stable period of little increase in thresholds between 6 and 12 weeks, then a loss of 20-15 db between 12 and 18 weeks of age
- only one of eleven homozygotes have normal ABR thresholds in both ears at 12 weeks of age

increased susceptibility to otitis media

incudomalleolar fusion
- fusion of the malleus and incus

middle ear effusion
- at 8 weeks the middle ear cavity is filled with an aqueous effusion containing amorphous tissue masses, and at 12 weeks it is filled with pus-like secretions and an amorphous tissue mass

middle ear polyps

tympanic membrane retraction

homeostasis/metabolism phenotype

abnormal mineral level
- at 7 weeks of age, mice on the acceleration diet show severe mineralization in the muzzle area, showing calcium and phosphorus in a 2:1 ratio, similar to that in endochondral bone and the presence of hydroxyapatite
- g vibrissae
- mice from mothers on the acceleration diet during pregnancy exhibit extensive mineralization in the aorta, the coronary and carotid arteries, the retina, the blood vessels of the liver, and in the kidneys
- mice from mothers on the acceleration diet during pregnancy exhibit extensive mineralization in the dermal sheath of vibrissae as early as 4 weeks of age and progresses with age, showing a 17.7-fold increase in mineral content of the muzzle skin containing vibrissae
- on a normal diet, mutants exhibit less mineralization in the dermal sheath of vibrissae
- on a normal diet, vascular mineralization is not seen until around 5 months of age compared to 4 weeks of age on the acceleration diet

calcinosis
- treatment in mice homozygous for the ages with stiffened joints 2 Jackson allele, which was assessed on the BALB/cJ backgroud
- feeding a high phosphorous/low magnesium diet from 4 weeks of age until assessment at 12 weeks of age increases the calcium deposits throughout all of the affected tissues and additionally in the liver but this is less severe than the response to the same treatment in mice homozygous for the ages with stiffened joints 2 Jackson allele, which was assessed on the BALB/cJ backgroud

decreased circulating phosphate level
- homozygotes have approximately 20% of normal plasma concentrations of PPi, with concomitant PPi:Pi ratio reduction

middle ear effusion
- at 8 weeks the middle ear cavity is filled with an aqueous effusion containing amorphous tissue masses, and at 12 weeks it is filled with pus-like secretions and an amorphous tissue mass

cardiovascular system phenotype

abnormal aorta morphology
- mice from mothers on the acceleration diet during pregnancy and also fed this diet exhibit extensive mineralization in the aorta

abnormal carotid artery morphology
- mice from mothers on the acceleration diet during pregnancy and also fed this diet exhibit extensive mineralization in the carotid arteries

abnormal coronary artery morphology
- mice from mothers on the acceleration diet during pregnancy and also fed this diet exhibit extensive mineralization in the coronary arteries

abnormal kidney arcuate artery morphology

abnormal liver vasculature morphology
- mice from mothers on the acceleration diet during pregnancy and also fed this diet exhibit mineralized blood vessels in the liver, but no mineralization in the liver parenchyma

abnormal stapedial artery morphology
- the wall of the stapedial artery is thicker than normal with excessive calcium deposition

calcified aorta
- seen in mice from mothers on the acceleration diet during pregnancy and also fed this diet

calcified artery
- mice from mothers on the acceleration diet during pregnancy and also fed this diet show calcification of the carotid and coronary arteries

immune system phenotype

increased susceptibility to otitis media

joint inflammation

osteoarthritis
- arthritis found in the spine at 12 weeks of age
- osteoarthritis found in many joints and joints are very stiff and unbendable at 7 months of age

osteomyelitis
- severe osteomyelitis of the joints and unusual synovial cysts found at 13 weeks of age

integument phenotype

abnormal skin adnexa morphology
- mice from mothers on the acceleration diet during pregnancy exhibit extensive mineralization in the dermal sheath of vibrissae as early as 4 weeks of age and shows progression with age, showing a 17.7-fold increase in mineral content of the muzzle skin containing vibrissae
- ntaining vibrissae
- on a normal diet, mutants exhibit less mineralization in the dermal sheath of vibrissae

abnormal snout skin morphology

abnormal vibrissa follicle morphology
- mineralization of the capsule of the follicles of the vibrissae is found at 7 months of age

calcified skin
- mice from mothers on the acceleration diet during pregnancy and fed the same diet exhibit extensive mineralization in the dermal sheath of vibrissae as early as 4 weeks of age which progresses with age
- severe calcification of the fibrous capsule surrounding the muzzle vibrissae by 15 weeks of age

limbs/digits/tail phenotype

abnormal elbow joint morphology
- dilated joint spaces and hyperplastic synovium in the elbows found at 11 weeks of age

abnormal knee joint morphology
- dilated joint spaces and hyperplastic synovium in the knees found at 11 weeks of age

liver/biliary system phenotype

abnormal liver vasculature morphology
- mice from mothers on the acceleration diet during pregnancy and also fed this diet exhibit mineralized blood vessels in the liver, but no mineralization in the liver parenchyma

mortality/aging

increased sensitivity to induced morbidity/mortality
- Normal - however, mice show normal lifespan on a normal diet
- pups from mothers on the acceleration diet during pregnancy and the placed on the same diet at weaning exhibit reduced lifespan, with more than 50% of mice dying spontaneously before the age of 6 weeks and only 4 of 28 mice surviving to 12 weeks of age

renal/urinary system phenotype

abnormal kidney arcuate artery morphology

abnormal kidney morphology
- mice from mothers on the acceleration diet during pregnancy and also fed this diet exhibit extensive mineralization in the kidneys, affecting primarily the medullary tubules and arcuate and renal arteries

skeleton phenotype

abnormal elbow joint morphology
- dilated joint spaces and hyperplastic synovium in the elbows found at 11 weeks of age

abnormal knee joint morphology
- dilated joint spaces and hyperplastic synovium in the knees found at 11 weeks of age

abnormal malleus morphology

abnormal round window morphology
- the round window membrane is thicker than normal and there is overossification of the reound window ridge

decreased joint mobility
- on an 'acceleration diet' rich in phosphorus and low in magnesium, mutants show accelerated stiffening of the joints and hobbling gait
- stiffening of the joints is seen by around 2 months of age, particularly the forepaws

incudomalleolar fusion
- fusion of the malleus and incus

joint inflammation

osteoarthritis
- arthritis found in the spine at 12 weeks of age
- osteoarthritis found in many joints and joints are very stiff and unbendable at 7 months of age

osteomyelitis
- severe osteomyelitis of the joints and unusual synovial cysts found at 13 weeks of age

vision/eye phenotype

abnormal retina morphology
- mice from mothers on the acceleration diet during pregnancy and also fed this diet exhibit extensive mineralization in the retina

calcified retina
- seen in mice from mothers on the acceleration diet during pregnancy and also fed this diet

Genotype: Enpp1^asj/Enpp1⁺
C57BL/6J-Enpp1/GrsrJ

cardiovascular system phenotype

abnormal renal artery morphology
- mineralization of the medulary tubules and arcuate and renal arteries is found in heterozygotes, not just homozygotes, when fed a diet rich in phosphorus and low in magnesium

homeostasis/metabolism phenotype

decreased circulating phosphate level
- heterozygotes have reduced levels of plasma PPi, approximately 60% of normal levels

renal/urinary system phenotype

abnormal renal artery morphology
- mineralization of the medulary tubules and arcuate and renal arteries is found in heterozygotes, not just homozygotes, when fed a diet rich in phosphorus and low in magnesium

References

Harris BS; Ward-Bailey PF; Yu H; Bergstrom DE; Bronson RT; Donahue LR. 2011. Ages with stiffened joints, A new mutation in Enpp1 MGI Direct Data SubmissionMGI: J:174912
Li Q; Guo H; Chou DW; Berndt A; Sundberg JP; Uitto J. 2013. Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy. Dis Model Mech 6(5):1227-35PubMed: 23798568 MGI: J:201689
Tian C; Harris BS; Johnson KR. 2016. Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis. PLoS One 11(12):e0168159PubMed: 27959908 MGI: J:251638

Additional - Enpp1^asj related

Technical Support

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Genotyping Protocols
- Restriction Enzyme Digest:Enpp1
- Pyrosequencing:Enpp1
- End Point Analysis:Enpp1-EP
- Sanger sequencing:Enpp1
- Genotyping resources and troubleshooting
Citation
When using the ages with stiffened joints mouse strain in a publication, please cite the originating article(s) and include JAX stock #012810 in your Materials and Methods section.

Animal Health Reports

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Also Known As:ages with stiffened joints

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Enpp1asj

Allele Symbol: Enpp1asj

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Enpp1asj related

Mammalian Phenotype Terms by Genotype

Genotype: Enpp1asj/Enpp1asjC57BL/6J-Enpp1/GrsrJ

behavior/neurological phenotype

cellular phenotype

craniofacial phenotype

growth/size/body region phenotype

hearing/vestibular/ear phenotype

homeostasis/metabolism phenotype

cardiovascular system phenotype

immune system phenotype

integument phenotype

limbs/digits/tail phenotype

liver/biliary system phenotype

mortality/aging

renal/urinary system phenotype

skeleton phenotype

vision/eye phenotype

Genotype: Enpp1asj/Enpp1+C57BL/6J-Enpp1/GrsrJ

cardiovascular system phenotype

homeostasis/metabolism phenotype

renal/urinary system phenotype

References

Additional - Enpp1asj related

Genotyping Protocols

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Enpp1^asj

Allele Symbol: Enpp1^asj

Genotype: Enpp1^asj related

Genotype: Enpp1^asj/Enpp1^asj
C57BL/6J-Enpp1/GrsrJ

Genotype: Enpp1^asj/Enpp1⁺
C57BL/6J-Enpp1/GrsrJ

Additional - Enpp1^asj related