Behavioral and pathological characterization of novel mouse models of the fatal neurodegenerative disorders, infantile, late infantile and juvenile Batten diseases

Mutations in the CLN1,CLN2 and CLN3 genes cause infantile, late infantile and juvenile Batten disease, respectively. CLN1 and CLN2 both encode soluble lysosomal enzymes, palmitoyl protein thioesterase 1 (PPT1) and tripeptidyl peptidase 1 (TPP1), whereas the gene product of CLN3 is an endosomal/lysosomal transmembrane protein with largely unknown function. Common disease-causing mutations in the CLN1,CLN2 and CLN3 genes are nonsense mutations, which result in premature stop codons. Premature stop codons cause mRNA degradation by the nonsense-mediated decay pathway to prevent the generation of potentially harmful, truncated proteins. The so-called nonsense suppressive or read-through drugs promote translation through premature stop codons, resulting full-length proteins, which may be fully or partly functional depending on the amino acid substitution for the stop codon. In order to test nonsense suppression therapy for infantile, late infantile and juvenile Batten diseases we have generated new transgenic mouse disease models that carry common disease-causing human CLN1,CLN2 and CLN3 nonsense mutations. The initial behavioral and neuropathological characterization of the Cln1R151X nonsense mutant mouse model has recently been published, and therapeutic studies with read-through drugs in Cln1R151X mice are in progress. We have just started the molecular, behavioral and pathological characterization of our novel nonsense mutant Cln2 and Cln3 mice.

Related Publications

Miller, JN, Kovács, AD, Pearce, D.A. (2015) The novel Cln1R151X mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Human Molecular Genetics 24: 185-196.

Thada, V, Miller, JN, Kovács AD, Pearce DA. (2016) Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1R151X mouse model of INCL. Journal of Cellular and Molecular Medicine 20: 381-385.

Cárcel-Trullols, J, Kovács, AD, Pearce DA (2015) Cell biology of the NCL proteins: What they do and don't do. Biochimica et Biophysica Acta 1852: 2242-2255.