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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
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Identification of novel pathogenic variants of CUBN in patients with isolated proteinuria
Huihui Yang1, Lanfen He1, Hongjian Gong2
1Department of Nephrology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Center), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
Molecular Genetics & Genomic Medicine
|March 15, 2024
Summary
Mutations in the cubilin (CUBN) gene can cause isolated proteinuria without anemia. This study identified new CUBN variants leading to non-progressive kidney disease, expanding knowledge of proteinuria.
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Proteinuria is a risk factor for chronic kidney disease, but not all forms are detrimental.
- Isolated proteinuria can result from cubilin (CUBN) gene mutations, distinct from Imerslund-Gräsbeck syndrome (IGS).
Purpose of the Study:
- To investigate the genetic basis of non-progressive isolated proteinuria in four patients.
- To characterize novel and known CUBN variants associated with isolated proteinuria.
Main Methods:
- Whole-exome sequencing (WES) and next-generation sequencing were performed.
- CUBN variants were analyzed using cDNA-PCR sequencing, immunohistochemistry, and minigene assays.
- In silico prediction tools and 3D protein modeling were utilized.
Main Results:
- Four patients presented with isolated proteinuria and normal or elevated eGFR, lacking IGS symptoms.
- Identified CUBN variants included a homozygous splice-site mutation causing exon skipping and premature termination.
- Other identified variants were compound heterozygous splice-site, missense, and reported mutations affecting specific CUB domains.
Conclusions:
- Specific CUBN mutations can cause non-progressive isolated proteinuria.
- This expands the known spectrum of CUBN variants and aids understanding of proteinuria.
- Findings contribute to understanding the relationship between proteinuria and renal function.
