Contribution of Individual Amino Acids to the RNA Binding Activity of the Wilms’ Tumor Suppressor Protein WT1

Weiss, Tristen C.; Romaniuk, Paul J.

doi:10.1021/bi801586a

Cited by 14 publications

(19 citation statements)

References 39 publications

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“…The former group of mutations comprised amino acids 434, 437, 445, 446, 462, and 464-467, positions of established relevance for DNA and RNA binding 25,26 (Swiss-Prot: P19544). Patients with mutations in these positions uniformly showed early-onset renal disease and rapid progression to renal failure.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype associations in WT1 glomerulopathy

Lipska

Ranchin

Iatropoulos

et al. 2014

Kidney International

129

151

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WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype-phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.

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Section: Discussionmentioning

confidence: 99%

Genotype–phenotype associations in WT1 glomerulopathy

Lipska

Ranchin

Iatropoulos

et al. 2014

Kidney International

129

151

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show abstract

“…Although conservative, this kind of amino acid substitution in critical residues is hypothesized to be of functional significance (11,12). Zf4 is important for binding, and the presence/absence of the "KTS" insertion seems to switch between DNA binding (ϪKTS) and RNA binding (ϩKTS) (13,14). The residue Arg403 is located in the alphahelix of Zf3.…”

Section: Discussionmentioning

confidence: 99%

A Novel WT1 Gene Mutation in a Three-Generation Family with Progressive Isolated Focal Segmental Glomerulosclerosis

Benetti¹,

Caridi²,

Malaventura³

et al. 2010

Clinical Journal of the American Society of Nephrology

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“…It is involved in regulation of cell survival, proliferation and differentiation [61,64]. There are four major isoforms of WT1, deriving from two different splicing events: the first causes a 17 amino acid insertion in exon 5 and the second inserts three amino acids at the end of exon 9, leading to a decreased DNA-binding and transcription factor ability and an increased RNA binding [65,66]. Some studies demonstrated that differential expression of isoforms may have a clinical significance in AML [67].…”

Section: Wt1 Mutationsmentioning

confidence: 99%

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Panuzzo

Signorino

Calabrese

et al. 2020

JCM

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Acute myeloid leukemia is mainly characterized by a complex and dynamic genomic instability. Next-generation sequencing has significantly improved the ability of diagnostic research to molecularly characterize and stratify patients. This detailed outcome allowed the discovery of new therapeutic targets and predictive biomarkers, which led to develop novel compounds (e.g., IDH 1 and 2 inhibitors), nowadays commonly used for the treatment of adult relapsed or refractory AML. In this review we summarize the most relevant mutations affecting tumor suppressor genes that contribute to the onset and progression of AML pathology. Epigenetic modifications (TET2, IDH1 and IDH2, DNMT3A, ASXL1, WT1, EZH2), DNA repair dysregulation (TP53, NPM1), cell cycle inhibition and deficiency in differentiation (NPM1, CEBPA, TP53 and GATA2) as a consequence of somatic mutations come out as key elements in acute myeloid leukemia and may contribute to relapse and resistance to therapies. Moreover, spliceosomal machinery mutations identified in the last years, even if in a small cohort of acute myeloid leukemia patients, suggested a new opportunity to exploit therapeutically. Targeting these cellular markers will be the main challenge in the near future in an attempt to eradicate leukemia stem cells.

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Contribution of Individual Amino Acids to the RNA Binding Activity of the Wilms’ Tumor Suppressor Protein WT1

Cited by 14 publications

References 39 publications

Genotype–phenotype associations in WT1 glomerulopathy

Genotype–phenotype associations in WT1 glomerulopathy

A Novel WT1 Gene Mutation in a Three-Generation Family with Progressive Isolated Focal Segmental Glomerulosclerosis

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

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