Complex Allele with Additive Gain-of-Function STING1 Variants in a Patient with Cavitating Lung Lesions and Aspergillosis

Guffroy, Aurélien; Dieudonné, Yannick; Gies, Vincent; Danion, François; Korganow, Anne‐Sophie; Tarabeux, Julien; Ruch, Yvon; Soulas‐Sprauel, Pauline; Giorgiutti, Stéphane; Wadier, Nadége; Gérard, Bénédicte; Nourisson, Elsa; Nathan, Nadia; Legendre, M.; Frémond, Marie-Louise; Letscher-Bru, Valérie; Kessler, Romain; Hansmann, Yves

doi:10.1007/s10875-022-01284-8

Cited by 4 publications

(3 citation statements)

References 5 publications

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“…Typically, this occurs in diseases following AD inheritance due to compound heterozygosity ( 30 , 31 ). Also for SAVI, complex allelic traits with two PV in cis , leading to additive gain of function, were described ( 11 , 12 ). For example, for adult-onset polycystic kidney disease, which is typically an AD trait, homozygosity of hypomorphic variants in the polycystic kidney disease 1 gene PKD1 may be disease causing, while heterozygous mutations lead to a mild phenotype with only minor renal cysts, altogether rather advocating for incomplete penetrance than for true AR inheritance ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic spectrum in recessive STING-associated vasculopathy with onset in infancy: Four novel cases and analysis of previously reported cases

et al. 2022

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Gain-of-function variants in the stimulator of interferon response cGAMP interactor 1 (STING1) gene cause STING-Associated Vasculopathy with onset in Infancy (SAVI). Previously, only heterozygous and mostly de novo STING1 variants have been reported to cause SAVI. Interestingly, one variant that only leads to SAVI when homozygous, namely c.841C>T p.(Arg281Trp), has recently been described. However, there are no entries in public databases regarding an autosomal recessive pattern of inheritance. Here, we report four additional unrelated SAVI patients carrying c.841C>T in homozygous state. All patients had interstitial lung disease and displayed typical interferon activation patterns. Only one child displayed cutaneous vasculitis, while three other patients presented with a relatively mild SAVI phenotype. Steroid and baricitinib treatment had a mitigating effect on the disease phenotype in two cases, but failed to halt disease progression. Heterozygous c.841C>T carriers in our analysis were healthy and showed normal interferon activation. Literature review identified eight additional cases with autosomal recessive SAVI caused by c.841C>T homozygosity. In summary, we present four novel and eight historic cases of autosomal recessive SAVI. We provide comprehensive clinical data and show treatment regimens and clinical responses. To date, SAVI has been listed as an exclusively autosomal dominant inherited trait in relevant databases. With this report, we aim to raise awareness for autosomal recessive inheritance in this rare, severe disease which may aid in early diagnosis and development of optimized treatment strategies.

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Section: Discussionmentioning

confidence: 99%

“…Unfortunately, most of them are not listed in public databases (e.g., ClinVar) ( 10 ). In addition, complex alleles with two PV in cis , causing an additive gain-of-function, have been described ( 11 , 12 ). Recently, a homozygous missense STING1 PV following autosomal recessive inheritance have been reported ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Phenotypic spectrum in recessive STING-associated vasculopathy with onset in infancy: Four novel cases and analysis of previously reported cases

et al. 2022

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“…The fourth cluster is located at the ligand-binding pocket such as G166E ( 73 ). Moreover, SAVI variants that combined two mutations were also found such as S102P/F279L, V155E/L170Q, and L189V/S280R ( 67 , 74 , 75 ). Based on the solved full-length human STING and active STING polymer, the cause of these gain-of-function mutations could be partially explained.…”

Section: Sting Structure and Its Related Autoimmune Diseasementioning

confidence: 99%

Activation of STING Based on Its Structural Features

et al. 2022

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The cGAS-cGAMP-STING pathway is an important innate immune signaling cascade responsible for the sensing of abnormal cytosolic double-stranded DNA (dsDNA), which is a hallmark of infection or cancers. Recently, tremendous progress has been made in the understanding of the STING activation mechanism from various aspects. In this review, the molecular mechanism of activation of STING protein based on its structural features is briefly discussed. The underlying molecular mechanism of STING activation will enable us to develop novel therapeutics to treat STING-associated diseases and understand how STING has evolved to eliminate infection and maintain immune homeostasis in innate immunity.

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DWL-4-140: A allene small molecule targeting STING that alleviates lupus-like phenotype in Trex1−/− mice

Kou

Deng

et al. 2023

Biomedicine & Pharmacotherapy

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Complex Allele with Additive Gain-of-Function STING1 Variants in a Patient with Cavitating Lung Lesions and Aspergillosis

Cited by 4 publications

References 5 publications

Phenotypic spectrum in recessive STING-associated vasculopathy with onset in infancy: Four novel cases and analysis of previously reported cases

Phenotypic spectrum in recessive STING-associated vasculopathy with onset in infancy: Four novel cases and analysis of previously reported cases

Activation of STING Based on Its Structural Features

DWL-4-140: A allene small molecule targeting STING that alleviates lupus-like phenotype in Trex1−/− mice

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