GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome
Tobias Hermle1,2, Ronen Schneider1, David Schapiro1
1Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Journal of the American Society of Nephrology : JASN
|July 1, 2018
Summary
New genetic discoveries reveal novel causes of steroid-resistant nephrotic syndrome (SRNS), a kidney disease. Mutations in GAPVD1 and ANKFY1 implicate RAB5 regulation in SRNS pathogenesis, advancing understanding of this condition.
Area of Science:
- Genetics
- Nephrology
- Molecular Biology
Background:
- Steroid-resistant nephrotic syndrome (SRNS) is a significant cause of chronic kidney disease (CKD).
- Existing knowledge of monogenic causes explains only a portion of SRNS cases, highlighting the need for further discovery.
Purpose of the Study:
- To identify novel monogenic causes of SRNS.
- To investigate the functional roles of newly identified genes and their mutations in disease pathogenesis.
Main Methods:
- Whole-exome sequencing was performed on 665 patients with SRNS.
- In vitro functional assays and complementary studies in Drosophila nephrocytes were used to evaluate gene and mutation significance.
Main Results:
- Conserved homozygous missense mutations in GAPVD1 and ANKFY1 were identified in families with SRNS.
- Both proteins interact with RAB5 and with each other; mutations affect RAB5 binding and podocyte function.
- GAPVD1 interacts with nephrin, and patient-derived mutations impair this interaction, impacting endocytosis and protein trafficking.
Conclusions:
- Mutations in GAPVD1 and likely ANKFY1 represent novel monogenic causes of nephrotic syndrome (NS).
- These findings implicate RAB5 regulation in the pathogenesis of human NS.
Related Concept Videos
01:24Nephrotic Syndrome I : Introduction
661
Nephrotic Syndrome is a chronic kidney disorder defined by clinical findings such as severe proteinuria, hypoalbuminemia, hyperlipidemia, and edema. These symptoms result from damage to the glomeruli, the kidney’s filtering units, increasing their permeability to proteins.Definition and Meaning:Proteinuria, defined as the loss of more than 3.5 grams of protein per day in adults, is a crucial feature of nephrotic syndrome. This condition is often accompanied by edema, the accumulation of...
661
01:26Nephrotic Syndrome II : Assessment and Medical Management
247
IntroductionNephrotic syndrome is a kidney disorder marked by excessive protein loss in the urine, leading to various systemic complications. This condition often results from damage to the glomeruli—the kidney's filtering units—causing proteinuria, low blood protein levels, and fluid retention. Understanding the assessment, diagnosis, and management of nephrotic syndrome is essential for effective treatment and prevention of further kidney damage.AssessmentPatient History: Document...
247
01:24Nephrotic Syndrome III : Nursing Management
336
Nursing management for nephrotic syndrome adapts as the disease progresses, with strategies evolving to address advancing symptoms and complications.Early-Stage Management In the early stages, nursing interventions for nephrotic syndrome resemble those used in managing acute glomerulonephritis, focusing on symptom monitoring, fluid balance, and managing mild to moderate edema.Vital Signs: Regularly monitor blood pressure, pulse, respiratory rate, and temperature to promptly identify...
336
01:39Mutations
94.6K
Overview
94.6K
01:35Mutations
44.6K
Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
44.6K
00:36Viral Mutations
39.9K
A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
39.9K