Human Molecular Genetics, 2002, Vol. 11, No. 22 2709-2721
© 2002 Oxford University Press
Cln3 
ex7/8 knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth
1Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA and 2The Jackson Laboratory, Bar Harbor, ME 04609, USA
Received May 17, 2002; Accepted August 16, 2002
Juvenile-onset neuronal ceroid lipofuscinosis (JNCL; Batten disease) features hallmark membrane deposits and loss of central nervous system (CNS) neurons. Most cases of the disease are due to recessive inheritance of an 
1 kb deletion in the CLN3 gene, encoding battenin. To investigate the common JNCL mutation, we have introduced an identical genomic DNA deletion into the murine CLN3 homologue (Cln3) to create Cln3 
ex7/8 knock-in mice. The Cln3 ex7/8 allele produced alternatively spliced mRNAs, including a variant predicting non-truncated protein, as well as mutant battenin that was detected in the cytoplasm of cells in the periphery and CNS. Moreover, Cln3 ex7/8 homozygotes exhibited accrual of JNCL-like membrane deposits from before birth, in proportion to battenin levels, which were high in liver and select neuronal populations. However, liver enzymes and CNS development were normal. Instead, Cln3 ex7/8 mice displayed recessively inherited degenerative changes in retina, cerebral cortex and cerebellum, as well as neurological deficits and premature death. Thus, the harmful impact of the common JNCL mutation on the CNS was not well correlated with membrane deposition per se, suggesting instead a specific battenin activity that is essential for the survival of CNS neurons.
* To whom correspondence should be addressed at: Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129 USA. Tel: +1 6177265089; Fax: +1 6177265735; Email: macdonam{at}helix.mgh.harvard.edu
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