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Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome
INTRODUCTION: Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of WT1. For wild-type WT1, 2 active splice donor sites in intron 9 cause a mixture of 2 essential transcripts (with or without lysine-threonine-serine [+/KTS or −KTS]), and imbalance of the +K...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484119/ https://www.ncbi.nlm.nih.gov/pubmed/34622098 http://dx.doi.org/10.1016/j.ekir.2021.07.010 |
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author | Tsuji, Yurika Yamamura, Tomohiko Nagano, China Horinouchi, Tomoko Sakakibara, Nana Ishiko, Shinya Aoto, Yuya Rossanti, Rini Okada, Eri Tanaka, Eriko Tsugawa, Koji Okamoto, Takayuki Sawai, Toshihiro Araki, Yoshinori Shima, Yuko Nakanishi, Koichi Nagase, Hiroaki Matsuo, Masafumi Iijima, Kazumoto Nozu, Kandai |
author_facet | Tsuji, Yurika Yamamura, Tomohiko Nagano, China Horinouchi, Tomoko Sakakibara, Nana Ishiko, Shinya Aoto, Yuya Rossanti, Rini Okada, Eri Tanaka, Eriko Tsugawa, Koji Okamoto, Takayuki Sawai, Toshihiro Araki, Yoshinori Shima, Yuko Nakanishi, Koichi Nagase, Hiroaki Matsuo, Masafumi Iijima, Kazumoto Nozu, Kandai |
author_sort | Tsuji, Yurika |
collection | PubMed |
description | INTRODUCTION: Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of WT1. For wild-type WT1, 2 active splice donor sites in intron 9 cause a mixture of 2 essential transcripts (with or without lysine-threonine-serine [+/KTS or −KTS]), and imbalance of the +KTS/−KTS ratio results in the development of FS. To date, 6 causative intron 9 variants have been identified; however, detailed transcript analysis has not yet been conducted and the genotype-phenotype correlation also remains to be elucidated. METHODS: We conducted an in vitro minigene splicing assay for 6 reported causative variants and in vivo RNA sequencing to determine the +KTS/−KTS ratio using patients’ samples. We also performed a systematic review of reported FS cases with a description of the renal phenotype. RESULTS: The in vitro assay revealed that although all mutant alleles produced −KTS transcripts only, the wild-type allele produced both +KTS and −KTS transcripts at a 1:1 ratio. In vivo RNA sequencing showed that patients’ samples with all heterozygous variants produced similar ratios of +KTS to −KTS (1:3.2−1:3.5) and wild-type kidney showed almost a 1:1 ratio (1:0.85). A systematic review of 126 cases clarified that the median age of developing ESKD was 16 years in all FS patients, and there were no statistically significant differences between the genotypes or sex chromosome karyotypes in terms of the renal survival period. CONCLUSION: Our study suggested no differences in splicing pattern or renal survival period among reported intron 9 variants causative of FS. |
format | Online Article Text |
id | pubmed-8484119 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-84841192021-10-06 Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome Tsuji, Yurika Yamamura, Tomohiko Nagano, China Horinouchi, Tomoko Sakakibara, Nana Ishiko, Shinya Aoto, Yuya Rossanti, Rini Okada, Eri Tanaka, Eriko Tsugawa, Koji Okamoto, Takayuki Sawai, Toshihiro Araki, Yoshinori Shima, Yuko Nakanishi, Koichi Nagase, Hiroaki Matsuo, Masafumi Iijima, Kazumoto Nozu, Kandai Kidney Int Rep Clinical Research INTRODUCTION: Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of WT1. For wild-type WT1, 2 active splice donor sites in intron 9 cause a mixture of 2 essential transcripts (with or without lysine-threonine-serine [+/KTS or −KTS]), and imbalance of the +KTS/−KTS ratio results in the development of FS. To date, 6 causative intron 9 variants have been identified; however, detailed transcript analysis has not yet been conducted and the genotype-phenotype correlation also remains to be elucidated. METHODS: We conducted an in vitro minigene splicing assay for 6 reported causative variants and in vivo RNA sequencing to determine the +KTS/−KTS ratio using patients’ samples. We also performed a systematic review of reported FS cases with a description of the renal phenotype. RESULTS: The in vitro assay revealed that although all mutant alleles produced −KTS transcripts only, the wild-type allele produced both +KTS and −KTS transcripts at a 1:1 ratio. In vivo RNA sequencing showed that patients’ samples with all heterozygous variants produced similar ratios of +KTS to −KTS (1:3.2−1:3.5) and wild-type kidney showed almost a 1:1 ratio (1:0.85). A systematic review of 126 cases clarified that the median age of developing ESKD was 16 years in all FS patients, and there were no statistically significant differences between the genotypes or sex chromosome karyotypes in terms of the renal survival period. CONCLUSION: Our study suggested no differences in splicing pattern or renal survival period among reported intron 9 variants causative of FS. Elsevier 2021-07-16 /pmc/articles/PMC8484119/ /pubmed/34622098 http://dx.doi.org/10.1016/j.ekir.2021.07.010 Text en © 2021 International Society of Nephrology. Published by Elsevier Inc. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Clinical Research Tsuji, Yurika Yamamura, Tomohiko Nagano, China Horinouchi, Tomoko Sakakibara, Nana Ishiko, Shinya Aoto, Yuya Rossanti, Rini Okada, Eri Tanaka, Eriko Tsugawa, Koji Okamoto, Takayuki Sawai, Toshihiro Araki, Yoshinori Shima, Yuko Nakanishi, Koichi Nagase, Hiroaki Matsuo, Masafumi Iijima, Kazumoto Nozu, Kandai Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome |
title | Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome |
title_full | Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome |
title_fullStr | Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome |
title_full_unstemmed | Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome |
title_short | Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome |
title_sort | systematic review of genotype-phenotype correlations in frasier syndrome |
topic | Clinical Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484119/ https://www.ncbi.nlm.nih.gov/pubmed/34622098 http://dx.doi.org/10.1016/j.ekir.2021.07.010 |
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