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Activation of inflammatory pathways in transcriptome from patients affected by limb girdle muscular dystrophy D2 (LGMDD2)

ABSTRACT: 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-κβ 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193662 | GEO | 2022/05/10

REPOSITORIES: GEO

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Project description:Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle magnetic resonance image (MRI), with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterised by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although interindividual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganisation. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients’ muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.

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Activation of inflammatory pathways in transcriptome from patients affected by limb girdle muscular dystrophy D2 (LGMDD2)

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