Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder

The late-infantile form of neuronal ceroid lipofuscinosis (LINCL) is a prog ressive and ultimately fatal neurodegenerative disease of childhood. The de fective gene in this hereditary disorder, CLN2, encodes a recently identifi ed lysosomal pepstatin-insensitive acid protease. To better understand the molecular pathology of LINCL, we conducted a genetic survey of CLN2 in 74 L INCL families. In 14 patients, CLN2 protease activities were normal and no mutations were identified, suggesting other forms of NCL. Both pathogenic a lleles were identified in 57 of the other 60 LINCL families studied. In tot al, 24 mutations were associated with LINCL, comprising six splice-junction mutations, 11 missense mutations, 3 nonsense mutations, 3 small deletions, and 1 single-nucleotide insertion. Two mutations were particularly common: an intronic G-->C transversion in the invariant AG of a 3' splice junction , found in 38 of 115 alleles, and a C-->T transition in 32 of 115 alleles, which prematurely terminates translation at amino acid 208 of 563. An Arg-- >His substitution was identified, which was associated with a late age at o nset and protracted clinical phenotype, in a number of other patients origi nally diagnosed with juvenile NCL.