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Case Reports
. 2024 Oct 2;45(1):20.
doi: 10.1007/s10875-024-01813-7.

MDA5 gain-of-function associated with a Glu794del mutation

Callie Wong  1 , Lukas Gerasimavicius  1 , Yanick J Crow  2   3 , Carolina Uggenti  1 ; E794del consortium
Collaborators, Affiliations
Case Reports

MDA5 gain-of-function associated with a Glu794del mutation

Callie Wong et al. J Clin Immunol. .
No abstract available

Keywords: Deletion mutation; Gain-of-function; IFIH1; Interferonopathy; MDA5.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A Low resolution cerebral CT imaging at age 22 months demonstrating dense calcification of the basal ganglia and at the grey-white matter junction bilaterally. B Interferon stimulated gene (ISG) mRNA expression in peripheral whole blood assessed using NanoString technology. The first number in brackets is the decimalized age at the time of sampling, and the second the interferon score (calculated according to the median fold change in relative quantification of the ISGs compared with 27 controls (blue bars; normal < 2.75)). C Simplified pedigree structure and mutation status (WT = wild-type). Circles and square indicate females and male, respectively. Filled shapes indicate affected status. D CLUSTAL Omega alignment of MDA5 homologues. The glutamine deleted by the NM_022168.4:c.2381_2383del mutation in IFIH1 is highlighted in yellow, and the recurrently mutated residue at position 779 in green. E IFIH1 expression (qPCR, n = 4). F MDA5 protein expression (WB, n = 3). G Colour change in Quanti-Blue solution (Left). SEAP activity (Right). H Composite interferon (IFN) score in HEK-Blue ISG cells transduced with the E794del mutant construct or the T331R or H927A constructs serving as positive and negative controls respectively (n = 4). I Expression of ISG15 before and after stimulation of HEK-Blue ISG cells with the dsRNA mimic poly(I:C), (n = 4). J The structural effects of the MDA5 E794 deletion were modelled in Rosetta, and their energetic impacts evaluated using the Relax application. The difference in Gibb’s free energy change for the complex (ΔΔGComplex) proved to be the most impacted by this deletion, demonstrating a lower ΔΔG value, stabilizing the protein interactions with dsRNA and the ADP ligand. PDB structure 7JL0 was used for the E794 visualization and deletion modelling. One way ANOVA with Dunnett’s multiple comparisons test **** = p < 0.0001, *** = p < 0.001, ** = p < 0.01, * = p < 0.05, ns = non specific
See this image and copyright information in PMC

References

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