Abstract
CLN3 Batten disease (CLN3 disease) is a pediatric lysosomal storage disorder that presents with progressive blindness, motor and cognitive decline, seizures, and premature death. CLN3 disease results from mutations in CLN3 with the most prevalent mutation, a 966 bp deletion spanning exons 7–8, affecting ~ 75% of patients. Mouse models with complete Cln3 deletion or Cln3Δex7/8 mutation have been invaluable for learning about both the basic biology of CLN3 and the underlying pathological changes associated with CLN3 disease. These models, however, vary in their disease presentation and are limited in their utility for studying the role of nonsense mediated decay, and as a consequence, in testing nonsense suppression therapies and read-through compounds. In order to develop a model containing a disease-causing nonsense point mutation, here we describe a first-of-its-kind Cln3Q352X mouse model containing a c.1054C > T (p.Gln352Ter) point mutation. Similar to previously characterized Cln3 mutant mouse lines, this novel model shows pathological deficits throughout the CNS including accumulation of lysosomal storage material and glial activation, and has limited perturbation in behavioral measures. Thus, at the molecular and cellular level, this mouse line provides a valuable tool for testing nonsense suppression therapies or read through compounds in CLN3 disease in the future.
Highlights
CLN3 Batten disease (CLN3 disease) is a pediatric lysosomal storage disorder that presents with progressive blindness, motor and cognitive decline, seizures, and premature death
CLN3 Batten disease (CLN3 disease), referred to as juvenile neuronal ceroid lipofuscinosis (JNCL), is an autosomal recessive disorder caused by mutations in CLN3
Nonsense mediated decay (NMD) typically occurs during the first translation of mutant transcript, where mutant mRNAs that contain premature termination codons (PTC) prohibit the ribosome from reaching and removing the exon junction complex, triggering the NMD signaling cascade[10]
Summary
CLN3 Batten disease (CLN3 disease) is a pediatric lysosomal storage disorder that presents with progressive blindness, motor and cognitive decline, seizures, and premature death. Mouse models with complete Cln[3] deletion or Cln3Δex7/8 mutation have been invaluable for learning about both the basic biology of CLN3 and the underlying pathological changes associated with CLN3 disease These models, vary in their disease presentation and are limited in their utility for studying the role of nonsense mediated decay, and as a consequence, in testing nonsense suppression therapies and read-through compounds. NMD is a growing target for therapeutic intervention through the use of read-through compounds, which promote translation through the PTC, or nonsense suppression therapies, which block the NMD signaling cascade, in several disease indications, including Batten disease[14,15]. Previous research in a nonsense point mutant CLN3 patient line (c.1054C > T (p.Gln352Ter)) revealed that CLN3Q352X mRNA expression could be increased via NMD inhibition by siRNA-mediated knockdown, opening the door to study the effects of nonsense suppression and read-through therapies using a relevant CLN3 point mutation
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