Human Molecular Genetics Advance Access originally published online on August 4, 2008
Human Molecular Genetics 2008 17(21):3332-3339; doi:10.1093/hmg/ddn228
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Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models
1 Center for Neural Development and Disease 2 Department of Biochemistry and Biophysics 3 Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 645, Rochester, NY 14642, USA 4 Molecular Medicine Unit, University College London (UCL) Institute of Child Health, London WC1N 1EH, UK
* To whom correspondence should be addressed. Tel: +1 5852731514; Fax: +1 5852761972; Email: david_pearce{at}urmc.rochester.edu
Received July 1, 2008; Accepted July 31, 2008
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
ex1-6 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 Cln3ex1-6 mouse brain. From the analysis of expressed Cln3ex1-6 mouse transcripts, combined with in silico prediction of the expected consequences of the Cln3ex1-6 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 Cln3ex1-6 mouse harbors a null Cln3 allele, and that it therefore represents a valid model for this disease.
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