| Summary: | Mutations in LRPPRC cause Leigh Syndrome French Canadian (LSFC), an early onset neurodegenerative disease, with differential tissue involvement. The molecular basis for tissue specificity in this disease remains unknown. LRPPRC, an RNA binding protein, forms a stable complex with SLIRP, which binds to, and stabilizes mitochondrial mRNAs. In cell culture and animal models, loss of LRPPRC function results in transcript-specific alterations in the steady-state levels of mitochondrial mRNAs and poly (A) tail length, the mechanisms for which are not understood. The poly (A) tail length of mitochondrial mRNAs has not been investigated in human tissues from heathy subjects or LSFC patients. Here we have mapped the 3′-termini of mature mitochondrial mRNAs in three tissues (skeletal muscle, heart, and liver) from a healthy individual and an LSFC patient. We show that the poly (A) tail length of mitochondrial mRNAs varies amongst tissues, and that the missense mutation in LRPPRC that causes LSFC results in tissue- and transcript-specific deadenylation of a subset of mitochondrial mRNAs, likely contributing the nature and severity of the biochemical phenotype in different tissues. We also found a relatively large fraction of short transcripts lacking a stop codon, some with short poly (A) tails, in patient tissue, suggesting that mutations in LRPPRC may also impair proper 3′ end processing of some mRNAs.
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