Targeted disruption of the Cln3 gene provides a mouse model for Batten disease

Batten disease, a degenerative neurological disorder with juvenile onset, i s the most common form of the neuronal ceroid lipofuscinoses. Mutations in the CLN3 gene cause Batten disease. To facilitate studies of Batten disease pathogenesis and treatment, a murine model was created by targeted disrupt ion of the Cln3 gene. Mice homozygous for the disrupted Cln3 allele had a n euronal storage disorder resembling that seen in Batten disease patients: t here was widespread and progressive intracellular accumulation of autofluor escent material that by EM displayed a multilamellar rectilinear/ fingerpri nt appearance. Inclusions contained subunit c of mitochondrial ATP synthase . Mutant animals also showed neuropathological abnormalities with loss of c ertain cortical interneurons and hypertrophy of many interneuron population s in the hippocampus. Finally, as is true in Batten disease patients, there was increased activity in the brain of the lysosomal protease Cln2/TPP-1. Our findings are evidence that the Cln3-deficient mouse provides a valuable model for studying Batten disease. (C) 1999 Academic Press.