PMC7820697_01
(A) Pedigree of the SAVI patients' family. (B-I) Chest CT for MA, showing diffused centrilobular emphysema and interlobar septal thickening in both lung fields associated with enlarged main pulmonary artery and its main branches. (B-II) Interval progression of diffuse emphysematous changes more marked in both lower lobes with honeycombing. Changes of pulmonary arterial hypertension. (B-III) CT chest of YA, showing diffused fine nodular opacities bilaterally with consolidation in both lungs bases posteriorly. The pulmonary trunk and major mediastinal vessels are unremarkable. (C) Crystallized structure of the human STING C-terminal domain bound to cyclic-di-GMP (PDB accession 4EMT). Top left: Front view of the STING dimer, with the view axis parallel to the membrane. The cyclic-di-GMP is shown as blue sticks in the center of the dimerization interface. R281 is shown as orange sticks. Top right: View of the STING dimer from the top, showing both appearances of R281. Bottom left: Zoom into the proximity of R281, showing neighboring residues that contribute to the presence of the hydrophilic patch on the protein surface and that might present clashes with the tryptophan substitution (shown as gray sticks). Bottom center: Surface electrostatic potential surrounding R281, with the protruding positive patch generated by the arginine, which is lost in the bottom-right picture after the substitution for tryptophan. (D) Gene expression for STING1, IFN-alpha and IFN-beta1 before and after treatment for patient MA. There is overexpression for IFN-beta1 in patients compared to non-affected individuals (SEM = 3.4). STING1 and IFN-alpha showed no significant increase in expression in patients compared to non-affected individuals. STING1 (SEM = 0.44) and IFN-alpha (SEM = 3.4). (E) IFN-beta1 plasma level of the patient MA before and after ruxolitinib treatment (SEM = 0.109).
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A CT scan of the chest was performed and displayed centrilobular emphysema and pulmonary hypertension ( Figure 1B ). Both parents and three of the siblings were heterozygous for the mutation ( Figure 1A ;  Figure 3 ). The mutated Arg281 is located on the surface of the STING1 cytosolic CTD ( Figure 1C , top), capping an exterior helix and creating a patch with a positive charge protruding from the protein surface ( Figure 1C , bottom). Nonetheless, the substitution could mildly affect the protein structure/function by altering the conformation of its containing helix or the interaction with its neighboring helix, which is a part of the dimerization interface of STING and is also adjacent to the cyclic-di-GMP binding site ( Figure 1C , top). The substitution could also disturb the potential interaction of this region with one or more STING binding partners by changing the local charge on the protein surface ( Figure 1C , bottom). Interestingly, treatment with Ruxolitinib suppressed the expression of IFN-beta1 in patients' PBMCs ( Figure 1D ) and dramatically lowered its serum levels ( Figure 1E ).
(A) Shows the gross phenotype of MA at 15 years of age and sister YA at 7 years of age. Figure shows the index case with nasal deviation. (B) Hand of MA showing mild acrocyanosis with leukonychia but no acro-necrosis. (C) shows eight healed hyperpigmented macules of various sizes on the back of MA, with a few showing central clearing. (D) Image of posterior-lateral scalp showing a large area of alopecia with central hypopigmentation. (E) YA with violaceous discoloration of the nasal cartilage. Pre-treatment; a large area of hair loss on the posterior lateral scalp with central hypopigmentation. (F) Hand of YA showing no clubbing or acro-necrosis. (G) Post-treatment; Reduction in the size of the area of hair loss with hair regrowth and a decrease in the hypopigmentation.
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At the age of 11, MA was admitted to King Saud University Medical City (KSUMC-KKUH) for the investigation of a violet-red skin rash (see  Figure 2 ). No oral ulcers or other mucocutaneous lesions were found ( Figure 2E ).
Segregation analysis for the STING1, NM_198282.3: c.841C>T variant.
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Both parents and three of the siblings were heterozygous for the mutation ( Figure 1A ;  Figure 3 ).
Relative Gene expression for STING1, IFNalpha and IFNbeta1 for the whole family before treatment. (A) qRT-PCR relative Quantification for Gene Expression for STING1, IFNalpha and IFNbeta1. There is over expression for IFNbeta1 in patients compared to non-affected individuals (SEM = 3.4). STING1 and IFNalpha showed no significant increase in expression in patients compared to non-affected individuals. STING1 (SEM = 0.44) and IFNalpha (SEM = 3.4). (B) IFN beta1 plasma level of the family before treatment.
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However, the gene expression and plasma levels of IFN-beta1 were significantly higher in the patients compared to carrier or non-carrier family controls ( Figure 4 ), suggesting the constitutive activation of the STING pathway.