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 PPi, 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).
