Osteopetrosis (op/op) is a new mutation in the mouse that is transmitted as an autosomal recessive linked with variant waddler (Va) on chromosome 12. Compared with normal littermates, young op/op mice have excessive accumulations of bone without marrow cavities, increases in bone matrix formation and concentrations of parafollicular cells of the thyroid, and are hypophosphatemic. Osteoclasts from op/op mice are small, few in number and have an abnormal cytoplasmic distribution of the lysosomal enzyme acid phosphatase. In contrast to the three other mutations that transmit osteopetrosis in mice, the skeletal signs of the disease slowly disappear in op/op animals after bone matrix formation declines about 6 weeks after birth from 145 percent to 20 percent of that in normal siblings. The main skeletal defect in op/op mice appears to be a severe restriction in bone remodeling that is capable of slowly removing the excessive skeletal mass characteristic of the disease only after bone formation has declined to one-fifth that of normal littermates.

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The "staggerer" mutant is recognized by its staggering gait, mild tremor, hypotonia, and small size. Symptoms develop during postnatal weeks 1 to 4 and remain stationary thereafter. The cerebellar cortex is grossly underdeveloped, with too few granule cells and unaligned Purkinje cells. Genetic linkage studies and neuropathological findings distinguish staggerer from other known mutants.

The neuronal ceroid lipofuscinoses (NCLs) comprise a set of at least 6 distinct human and an unknown number of animal diseases characterized by storage of proteolipids in lysosomes of many cell types. By unknown mechanisms, this accumulation leads to or is associated with severe neuronal and retinal degeneration. The genes for 3 human NCLs, infantile, late infantile, and juvenile, have been cloned. The first murine form of NCL, the motor neuron degeneration (mnd) mouse, has been described and mapped to proximal Chromosome 8. Here we describe a second genetic variant of NCL in the mouse, neuronal ceroid lipofuscinosis, nclf. These mice exhibited a phenotype that was almost exactly the same as that observed in mnd/mnd mice. Homozygous nclf mice developed progressive retinal atrophy early in life and become paralyzed at around 9 months of age. They accumulated luxol fast blue staining material in cytoplasm of neurons and many other cell types. Ultrastructurally, affected lysosomes had a "finger print pattern" with membranous material arranged in "pentalaminar" patterns. Affected mice developed severe cerebral gliosis in late stages of their disease. They also had severe Wallerian degeneration of long tracts in spinal cord and brain stem, lesions that accounted for the distinctive upper motor neuron signs displayed by both nclf/nclf and mnd/mnd mice. By crossing nclf/nclf mice with CAST/Ei mice, linkage analysis of nclf with respect to SSLP markers was performed, showing that nclf is located on Chromosome 9 between D9Mit164 and D9Mit165, in a region that is homologous with human Ch 15q21, where the gene for one variant of late infantile NCL, CLN6, recently has been mapped. The genes for two proteolipids known to be stored in lysosomes of animals and people with NCL were also mapped in this study and found not to map to the mnd or nclf loci nor to any mouse locus homologous to any known human NCL disease locus.

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