C57BL/6J-Enpp1^asj/GrsrJ

Stock number: 012810
Product name: ages with stiffened joints
Research areas: Developmental Biology Research, Endocrine Deficiency Research, Internal/Organ Research

Description

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.

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.

Allele

Symbol: Enpp1^asj
Name: ages with stiffened joints
MGI accession ID: MGI:3785162
Generation method: Chemically induced (ENU)
Marker symbol: Enpp1
Marker name: ectonucleotide pyrophosphatase/phosphodiesterase 1
Marker synonyms: 4833416E15Rik; ARHR2; CD203c; COLED; E-NPP1; Ly-41; M6S1; NPP1; NPPS; Pc1; PC-1; Pca; PCA1; Pca-1; PDNP1; twy
Chromosome: 10
Strain of origin: C57BL/6J
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.