NEURONAL CEROID-LIPOFUSCINOSIS (NCLF), A NEW DISORDER OF THE MOUSE LINKED TO CHROMOSOME-9

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 unknow n mechanisms, this accumulation leads to or is associated with severe neuronal and retinal degeneration, The genes for 3 human NCLs, infanti le, late infantile, and juvenile, have been cloned, The first murine f orm of NCL, the motor neuron degeneration (mnd) mouse, has been descri bed and mapped to proximal Chromosome 8, Here we describe a second gen etic 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 progres sive retinal atrophy early in life and become paralyzed at around 9 mo nths of age. They accumulated luxol fast blue staining material in cyt oplasm of neurons and many other cell types, Ultrastructurally, affect ed lysosomes had a ''finger print pattern'' with membranous material a rranged in ''pentalaminar'' patterns. Affected mice developed severe c erebral gliosis in late stages of their disease, They also had severe Wallerian degeneration of long tracts in spinal cord and brain stem, l esions that accounted for the distinctive upper motor neuron signs dis played 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 marke rs was performed, showing that nclf is located on Chromosome 9 between D9Mit164 and D9Mit165, in a region that is homologous with human Ch 1 5q21, where the gene for one variant of late infantile NCL, CLN6, rece ntly has been mapped, The genes for two proteolipids known to be store d 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 l ocus homologous to any known human NCL disease locus. (C) 1998 Wiley-L iss.