GSE193662
Activation of inflammatory pathways in transcriptome from patients affected by limb girdle muscular dystrophy D2 (LGMDD2)
LGMDD2 is a rare form of muscular dystrophy characterized by a heterozygous deletion within the TNPO3 gen, firstly reported in a large Spanish family in 2001. TNPO3-wildtype is involved in the nuclear import of the essential splicing factors, a function altered in the mutated protein. Our group has shown that both TNPO3-wildtype and TNPO3-mutated proteins are translated in these patients. Besides its role in LGMDD2 disease, TNPO3 is also a HIV-1 co-factor but the mechanism underlying its antiviral action is still controversial. In an attempt to connect both LGMDD2 disease and HIV-1 infection, we demonstrated that PBMCs from LGMDD2 patients are refractory to in vitro HIV-1 infection due to a deficient viral integration subsequent to a deficient transport of the splicing factor CPSF6, due to TNPO3 mutation. The accumulation of HIV-1 capsid and retrotranscribed DNA in the cytosol may trigger anti-HIV inflammatory responses, therefore enhancing the blockade of HIV-1 replication. Further characterization of the crosstalk between HIV-1 infection and LGMDD2 disease may contribute to a better understanding of cellular alterations occurring in subjects living with LGMDD2. To this regard, here we show a high-throughput transcriptome profiling of PBMCs from LGMDD2 patients compared to their non-affected relatives. The differentially expressed genes were up-regulated and included G protein-coupled receptor binding chemokines, zinc ion binding proteins and metalloendopeptidases. The functional annotation showed an enrichment in immune response and inflammation pathways including IL-17, TNF, NOD-like receptor, TLR receptor, and NF-?ß signaling pathways, which are also known to be altered during HIV-1 infection. In summary, a holistic perspective of cellular changes occurring during LGMDD2 pathology is shown here providing new factors in this muscular dystrophy that may be considered in the design of new therapeutic strategies. Overall design: mRNA profiles of PMBCs collected from individuals affected by limb girdle muscular dystrophy D2 (LGMDD2) compared with their non-affected relatives