title: A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy.
abstract: The cellular quality control systems enable surveillance and selective degradation of nonsense, nonstop, and no-go mRNAs. In the case of nonstop mRNA, different mechanisms of nonstop-mediated decay (NSD) have been described for bacteria, yeast and mammals, but the molecular consequences of nonstop mutations have been examined in only few cases of human disease. We describe a novel homozygous nonstop mRNA mutation (c.1416delC) in the TYMP gene encoding thymidine phosphorylase, in a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In contrast to previous reports showing selective decay of pathogenic nonstop mRNAs, quantitative real-time PCR and 3'-RACE-RFLP analysis revealed unreduced nonstop mRNA levels in our patient and 2 heterozygous carriers of the mutation. The absence of thymidine phosphorylase protein in the homozygous patient, together with the partial decrease in levels of this protein in 2 carriers suggest that the main control system in this case resides at the translational or post-translational levels rather than through NSD. This is the first report showing an absence of NSD in a human disease, revealing that this surveillance mechanism has exceptions in vivo.
authors.affiliation: Laboratori of Neuromuscular and Mitochondrial Disorders, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Torres-Torronteras
authors.forename: Agustí
authors.initials: A
authors.lastname: Rodriguez-Palmero
authors.forename: Tomàs
authors.initials: T
authors.lastname: Pinós
authors.forename: Anna
authors.initials: A
authors.lastname: Accarino
authors.forename: Antoni L
authors.initials: AL
authors.lastname: Andreu
authors.forename: Guillem
authors.initials: G
authors.lastname: Pintos-Morell
authors.forename: Ramon
authors.initials: R
authors.lastname: Martíí
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D005260:Female; D006720:Homozygote; D006801:Humans; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D013939:Thymidine Phosphorylase / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase