A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy

Javier Torres-Torronteras (1) , Agustí Rodriguez-Palmero (2) , Tomàs Pinós (1) , Anna Accarino (3) , Antoni Lluís Andreu (1) , Guillem Pintos-Morell (2) , Ramon Martí (4)

1 Laboratory of Mitochondrial Disorders
2 Pediatrics Department
3 Gastroenterology Department
4 Laboratory of Mitochondrial Disorders

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.

Mots clés: Life Sciences

Javier Torres-Torronteras, Agustí Rodriguez-Palmero, Tomàs Pinós, Anna Accarino, Antoni Lluís Andreu, et al.. A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy. Human Mutation, 2011, 32 (4), ⟨10.1002/humu.21447⟩. ⟨hal-00613761⟩