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Juvenile neuronal ceroid lipofuscinoses (JNCL), commonly known as Batten disease, is a progressive neurodegenerative disorder of childhood characterized by blindness, seizures, motor and cognitive decline, leading to death in early adulthood. Mutations within the CLN3 gene, which encodes a putative lysosomal protein of unknown function, are the underlying cause of JNCL. Over 85% of JNCL patients harbor a 1 kb deletion that is predicted to result in a truncated CLN3 protein and is presumed to be a null mutation. A recent study by Kitzmuller et al. (1) suggested that the 1 kb deletion-associated truncated protein may have partial function, and proposed that JNCL is a mutation-specific disease. In addition, the validity of the original and most widely utilized JNCL mouse model, the Cln3(Deltaex1-6) mouse, as a true null mutant was questioned. We report a substantial decrease in the transcript level of the truncated CLN3 gene product in cells from 1 kb deletion patients. We contend that the truncated CLN3 protein is unlikely to be expressed in JNCL patients since cellular quality control mechanisms at the RNA and protein levels are likely to degrade the mutant transcript and polypeptides. Moreover, we present analysis identifying the expressed transcripts present in Cln3(Deltaex1-6) mouse brain. From the analysis of expressed Cln3(Deltaex1-6) mouse transcripts, combined with in silico prediction of the expected consequences of the Cln3(Deltaex1-6) mutation on these transcripts, we argue that aberrant Cln3 proteins are unlikely to be expressed in this disease model. Taken together our results indicate that the most common mutation associated with JNCL results in a loss of functional CLN3, that the Cln3(Deltaex1-6) mouse harbors a null Cln3 allele, and that it therefore represents a valid model for this disease.

Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models