Cln^Δex7/8 knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth

Juvenile-onset neuronal cerold 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^Δex7/8 knock-in mice. The Cln3Δ^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^Δex7/8 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, Cln^Δex7/8 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.