A mouse gene knockout model for juvenile ceroid-lipofuscinosis (batten disease)

Abstract

The human hereditary ceroid-lipofuscinoses are a group of autosomal recessively inherited diseases characterized by massive accumulations of autofluorescent lysosomal storage bodies in the cells of many tissues and by neuronal degeneration throughout the central nervous system. There are a number of clinically and genetically distinct forms of ceroid-lipofuscinosis, the most common of which is the juvenile type, also known as Batten disease and CLN3. To study the mechanisms that lead to pathology in CLN3 and to evaluate potential therapies, a mouse model has been generated by targeted disruption of the mouse ortholog of the CLN3 gene (Cln3). As in affected humans, mice homozygous for the disrupted Cln3 allele show accumulation of autofluorescent storage material in neurons and other cell types. The storage material consists of membrane-bounded intracellular inclusions with ultrastructural features typical of the ceroid-lipofuscinoses. The accumulation of this storage material validates the Cln3 knockout mice as a model for the human disorder.

Disruption ofPPT1orPPT2causes neuronal ceroid lipofuscinosis in knockout mice

“…Together with the current study, genetic mouse models (two engineered and two naturally occurring) now exist for four of the eight forms of human NCL (19)(20)(21)(22)(23). Of these, the current model is among the most severe, with an onset clearly earlier than the CLN3 knockout (19,20), the nclf mouse [which likely represents a mouse model for NCL-6 (23)], and the mnd mouse [which represents NCL-8, or EPMR (progressive epilepsy with mental retardation) or ''Northern'' epilepsy] (22). The only possible exception is the mnd mouse on the AKR background, which has an onset by 4.5-5 mo and death by 7 mo (24).…”

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

“…To gain a better understanding the mechanisms underlying the disease pathology and to test potential approaches to therapy, it is important that a suitable animal model for JNCL be developed. Toward this end, three laboratories have generated mice with null mutations in the Cln3 gene (Cotman et al, 2002;Katz et al, 1999;Mitchison et al, 1999). Of these models, that described in the present study is the only one with the mutation on a pure C57BL/6J stain background.…”

“…The Cln3 -/-mouse model for juvenile NCL was generated by gene targeting in RW4 mouse embryonic stem cells as previously described (Katz et al, 1999), and the knockout mice were subsequently backcrossed to the C57BL/6J strain for more than 15 generations. To confirm that the Cln3 -/-mice were congenic to normal C57BL/6J animals over the entire genome except the region immediately surrounding the Cln3 gene, the founder mice were genotyped at 110 microsatellite loci that are polymorphic between the C57BL/6J and 129Sv/J (RW4) strains and that span the mouse genome at approximately 15 cM intervals (MaxBax panel, Charles River).…”

“…Animal models could be of great value in developing a better understanding of the mechanisms underlying neuropathology in JNCL and in developing therapies for this disorder. Three mouse Cln3 knockout models have been created (Cotman et al, 2002;Katz et al, 1999;Mitchison et al, 1999) that could be useful in developing therapeutic interventions if they exhibit quantifiable signs of disease. Experiments were performed to determine whether a homozygous Cln3 knockout mutation in mice resulted phenotypic alterations that resembled the human disease phenotype.…”

Neuronal ceroid lipofuscinosis/Batten disease: the lysosomal proteinoses

“…Mouse models have also been created for juvenile Batten (CLN3) disease. 10,11 Two naturally occurring NCL models, the mnd mouse and nclf mouse, are known to correspond to the human CLN8 and CLN6 genes, respectively. 2,3 Mouse models will surely facilitate a better understanding and the development of treatments for these disorders.…”