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Background <p>In this work, we describe the clinical and functional changes in a family with a novel type I interferonopathy phenotype which we suggest could be associated with a <i>TRIM28</i> variant, presenting with chilblains, skin ulceration, lipodystrophy and calcinosis. TRIM28 has multiple roles in regulating human health and disease, which include DNA repair and anti-viral response. The latter includes negative regulation of IRF7, one of the master regulators of the interferon response.</p> Methods <p>Whole exome sequencing and targeted panel sequencing was performed on DNA extracted from peripheral blood. Functional work included gene (qPCR), protein (WB) and cytokine (MSD and SIMOA) expression studies. Transfection studies of siRNA in control Human Dermal Fibroblast Cells (HDFCs) using RNAiMAX and of wild-type protein in patient HDFCs using FuGENE HD were also performed.</p> Results <p>Analysis of WES data according to a dominant model with incomplete penetrance revealed <i>TRIM28</i> c.A623G; p.Y208C in the proband of Family A and his mildly affected mother. Gene expression studies revealed persistent elevation of interferon inducible proteins including increased gene as well as protein expression of IRF7. Cytokine measurements revealed a marked elevation of pro-inflammatory cytokines particularly IFNβ in affected individuals. A good clinical and functional response to treatment with baricitinib was documented, however the proband subsequently died of septic complications. TRIM28-siRNA transfection into control HDFCs resulted in changes in gene, protein and cytokine expression similar to those seen in the proband. Transfection of a wild-type pEGFP-<i>TRIM28</i> plasmid into the proband’s HDFCs achieved partial rescue of the cellular phenotype.</p> Discussion <p>We describe a novel and severe interferonopathy potentially associated with an autosomal dominant <i>TRIM28</i> variant with an incomplete penetrance disease model, presenting with skin ulceration, calcinosis, high interferon scores, and upregulation of IRF7. Pathogenicity was supported by <i>TRIM28</i> gene silencing in healthy HDFCs. Polymorphisms in other genes such as <i>ITGAM</i> could modulate penetrance and expressivity.</p>

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An interferonopathy associated with a monoallelic variant in TRIM28

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月25日

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  • Sonia Melo Gomes,
  • Ebun Omoyinmi,
  • Ying Hong,
  • Gillian Rice,
  • Luis Seabra,
  • Vincent Bondet,
  • Darragh Duffy,
  • Glenn Anderson,
  • Florence Adams,
  • Fionnuala McMorrow,
  • Charalampia Papadopoulou,
  • J. A. Melo Gomes,
  • Paul Brogan

摘要

Background

In this work, we describe the clinical and functional changes in a family with a novel type I interferonopathy phenotype which we suggest could be associated with a TRIM28 variant, presenting with chilblains, skin ulceration, lipodystrophy and calcinosis. TRIM28 has multiple roles in regulating human health and disease, which include DNA repair and anti-viral response. The latter includes negative regulation of IRF7, one of the master regulators of the interferon response.

Methods

Whole exome sequencing and targeted panel sequencing was performed on DNA extracted from peripheral blood. Functional work included gene (qPCR), protein (WB) and cytokine (MSD and SIMOA) expression studies. Transfection studies of siRNA in control Human Dermal Fibroblast Cells (HDFCs) using RNAiMAX and of wild-type protein in patient HDFCs using FuGENE HD were also performed.

Results

Analysis of WES data according to a dominant model with incomplete penetrance revealed TRIM28 c.A623G; p.Y208C in the proband of Family A and his mildly affected mother. Gene expression studies revealed persistent elevation of interferon inducible proteins including increased gene as well as protein expression of IRF7. Cytokine measurements revealed a marked elevation of pro-inflammatory cytokines particularly IFNβ in affected individuals. A good clinical and functional response to treatment with baricitinib was documented, however the proband subsequently died of septic complications. TRIM28-siRNA transfection into control HDFCs resulted in changes in gene, protein and cytokine expression similar to those seen in the proband. Transfection of a wild-type pEGFP-TRIM28 plasmid into the proband’s HDFCs achieved partial rescue of the cellular phenotype.

Discussion

We describe a novel and severe interferonopathy potentially associated with an autosomal dominant TRIM28 variant with an incomplete penetrance disease model, presenting with skin ulceration, calcinosis, high interferon scores, and upregulation of IRF7. Pathogenicity was supported by TRIM28 gene silencing in healthy HDFCs. Polymorphisms in other genes such as ITGAM could modulate penetrance and expressivity.