A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

Milillo, Annamaria; Carpia, Francesca La; Costanzi, Stefano; D'Urbano, Vanessa; Martini, Maurizio; Lanuti, Paola; Vischini, Gisella; Larocca, Luigi Maria; Marchisio, Marco; Miscia, Sebastianó; Amoroso, Antonio; Gurrieri, Fiorella; Sangiorgi, Eugenio

doi:10.1038/ejhg.2015.52

Cited by 16 publications

(13 citation statements)

References 25 publications

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“…& IgA disease. About 15% of all cases of IgA disease have another affected family member [80] and although GWAS analyses have identified chromosomal loci, relatively few genes have been identified [81].…”

Section: Biallelic and Digenic Mutations Affect The Clinical Phenotypmentioning

confidence: 99%

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

et al. 2018

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Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.

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Section: Biallelic and Digenic Mutations Affect The Clinical Phenotypmentioning

confidence: 99%

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

et al. 2018

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“…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). So, we hypothesized that variants in some pathways caused by TRPC6 mutations are risk factors for the development of immune-complex deposition nephropathy.…”

Section: Discussionmentioning

confidence: 93%

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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“…The increasing number of larger GWASs in different populations has unveiled numerous IgAN-associated loci, including complement factor H-related (CFHR) genes [49][50][51] , or those encoding defensing (DEFA) [47,52] , HLA [53] , sprouty RTK signaling antagonist 2 (SPRY2) [54] , vav guanine nucleotide exchange factor 3 (VAV3) [46] , core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 (C1GALT1) [55] , and tumor necrosis factor superfamily member 13 (TNFSF13) [56] .…”

Section: Iga Nephropathymentioning

confidence: 99%

“…They reported that the allelic frequencies of the variants within ST6GAL1 (encoding ST6 beta-galactoside alpha-2,6sialyltransferase 1), ACCS (encoding 1-aminocyclopropane-1-carboxylate synthase homolog), and DEFA correlated with geographical variations in IgAN prevalence. Milillo et al [54] reported that a SPRY2 mutation inhibited the mitogen-associated protein kinase/extracellular signal-related kinase pathway, which was associated with an autosomal dominant form of IgAN. Gale et al [55] reported that a common variation in C1GALT1 influenced galactose-deficient IgA1 levels in the population, which was independently associated with the risk of progressive IgAN.…”

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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A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

Cited by 16 publications

References 25 publications

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

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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