Multiple rare genetic variants co‐segregating with familial IgA nephropathy all act within a single immune‐related network

Cox, Sharon Natasha; Pesce, Francesco; Moustafa, Julia S. El-Sayed; Sallustio, Fabio; Serino, Grazia; Kkoufou, C; Giampetruzzi, Annalisa; Ancona, Nicola; Falchi, Mario; Fp, Schena

doi:10.1111/joim.12565

Cited by 20 publications

(19 citation statements)

References 57 publications

(107 reference statements)

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“…The role of MAPK and PI3K/Akt signalling on IgAN's pathophysiology have been described in previous studies (38)(39)(40)(41) . We therefore focussed on validating key components of the TGF-β and Wnt signaling pathways with less literature support and where CARNIVAL and GSEA provided opposite results.…”

Section: Fluorescence Immunohistology Detection Of Rhoa and β-Cateninmentioning

confidence: 83%

From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

Liu

Trairatphisan

Gjerga

et al. 2019

Preprint

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While gene expression profiling is commonly used to gain an overview of cellular processes, the identification of upstream processes that drive expression changes remains a challenge. To address this issue, we introduce CARNIVAL, a causal network contextualization tool which derives network architectures from gene expression footprints. CARNIVAL (CAusal Reasoning pipeline for Network identification using Integer VALue programming) integrates different sources of prior knowledge including signed and directed protein-protein interactions, transcription factor targets, and pathway signatures. The use of prior knowledge in CARNIVAL enables capturing a broad set of upstream cellular processes and regulators, leading to a higher accuracy when benchmarked against related tools. Implementation as an integer linear programming (ILP) problem guarantees efficient computation. As a case study, we applied CARNIVAL to contextualize signaling networks from gene expression data in IgA nephropathy, a condition that can lead to chronic kidney disease. CARNIVAL identified specific signaling pathways and associated mediators dysregulated in IgAN including WNT and TGF-β, that we subsequently validated experimentally. These results demonstrated how CARNIVAL generates hypotheses on potential upstream alterations that propagate through signaling networks, providing insights into diseases.

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Section: Fluorescence Immunohistology Detection Of Rhoa and β-Cateninmentioning

confidence: 83%

From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

Liu

Trairatphisan

Gjerga

et al. 2019

Preprint

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“…Cox et al identified 23 genes with candidate pathogenic variants functionally related to a large network of immune-related pathways. They speculated that the IgAN disease status may be affected by a series of mutations that affect immune-related networks (25). Milillo et al identified the SPRY2 gene related to IgAN, which is part of the MAPK/ERK pathway (26).…”

Section: Discussionmentioning

confidence: 99%

Two Children With Novel TRPC6 Spontaneous Missense Mutations and Atypical Phenotype: A Case Report and Literature Review

Wang

Ren

et al. 2020

Front. Pediatr.

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Background: The phenotypes of TRPC6 mutations have been reported mainly in familial and sporadic focal segmental glomerulosclerosis (FSGS), which can occur in both adults and children. Herein, we report on two children with novel TRPC6 spontaneous missense mutations associated with immune complex-mediated glomerulonephritis and minor glomerular abnormality (MGA) that showed to be resistant to corticosteroids and other immunosuppressants. Case Presentation: A 9-year-old girl presented with steroid-resistant nephrotic syndrome (SRNS), while another 11-year-old boy developed proteinuria at 7 years old. Treatment with a variety of immunosuppressants had no effect, and the renal biopsy showed immune complex-mediated glomerulonephritis and MGA. No members of their family were clinically affected. Genetic testing was performed in the two patients, revealing two novel spontaneous missense mutations in TRPC6-N110S and P112R. The girl developed end-stage renal disease (ESRD) 5 months after onset while the boy continued to have sub-nephrotic range proteinuria and normal creatinine. Conclusions: Two novel TRPC6 mutations were associated with the atypical phenotype-immune complex-mediated glomerulonephritis and MGA, rather than FSGS as previously reported. Their rates of disease progression are different. Genetic testing is helpful to identify the etiology and avoid the side effects brought on by immunosuppressants.

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“…Multiple rare variants participating in a common network can influence disease susceptibility. Future investigations might explore the development of combined biomarkers to generate a prognostic model which can usher into potential genomic biomarkers and drug targets for personalized therapy [58] .…”

Section: Iga Nephropathymentioning

confidence: 99%

Genomic biomarkers for chronic kidney disease: the first step towards personalized medicine?

Cao¹,

Zhou²,

Liu³

2019

JTGG

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With the prevalence of end stage renal disease steadily increasing, chronic kidney disease (CKD) represents an impending public healthcare challenge. Classical diagnostic biomarkers of CKD, including creatinine, have low sensitivity and specificity. Thus, novel diagnostic and prognostic biomarkers for patients at high risk of early-stage progression are urgently needed. Personalized medicine approaches generally stratify patients according to their biological or genomic make-up. Targeted clinical trials require more precise identification of these subgroups. The use of new biomarkers obtained via high-throughput technologies is expected in future, accompanied by vast improvements in computational power applied in genomics, proteomics, and metabolomics studies using biological fluids and renal biopsy tissue. Genomic biomarkers may not only provide additional information regarding the etiology and mechanisms underlying CKD progression, but may also enable early diagnosis and the selection of appropriate drugs, thereby personalizing therapy. This review discusses commonly used research methods in genomic medicine and summarizes currently available genomic biomarkers in inherited and acquired CKD.

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Multiple rare genetic variants co‐segregating with familial IgA nephropathy all act within a single immune‐related network

Cited by 20 publications

References 57 publications

From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

Two Children With Novel TRPC6 Spontaneous Missense Mutations and Atypical Phenotype: A Case Report and Literature Review

Genomic biomarkers for chronic kidney disease: the first step towards personalized medicine?

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