title: The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis.
abstract: Neuronal ceroid lipofuscinosis (NCL), commonly referred to as Batten disease, is a group of autosomal recessive neurodegenerative diseases of childhood characterized by seizures, blindness, motor and cognitive decline and premature death. Currently, there are over 400 known mutations in 14 different genes, leading to five overlapping clinical variants of NCL. A large portion of these mutations lead to premature stop codons (PTCs) and are predicted to predispose mRNA transcripts to nonsense-mediated decay (NMD). Nonsense-mediated decay is associated with a number of other genetic diseases and is an important regulator of disease pathogenesis. We contend that NMD targets PTCs in NCL gene transcripts for degradation. A number of PTC mutations in CLN1, CLN2 and CLN3 lead to a significant decrease in mRNA transcripts and a corresponding decrease in protein levels and function in patient-derived lymphoblast cell lines. Inhibiting NMD leads to an increased transcript level, and where protein function is known, increased activity. Treatment with read-through drugs also leads to increased protein function. Thus, NMD provides a promising therapeutic target that would allow read-through of transcripts to enhance protein function and possibly ameliorate Batten disease pathogenesis.
authors.affiliation: Sanford Children’s Health Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA
authors.forename: Jake N
authors.initials: JN
authors.lastname: Miller
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Chan
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018389:Codon, Nonsense; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D023061:Gene Order; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000378:metabolism; D059365:Nonsense Mediated mRNA Decay; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000091346:Tripeptidyl-Peptidase 1
chemical_list: C105199:CLN3 protein, human; D018389:Codon, Nonsense; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D000091346:Tripeptidyl-Peptidase 1; D013869:Thiolester Hydrolases; C416054:PPT1 protein, human; C095299:palmitoyl-protein thioesterase; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human
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