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Ana C. Onuchic-Whitford, MD

Neptune Grant Awardee

Ana Claudia Onuchic-Whitford, MD, is a nephrologist at Brigham and Women’s Hospital and an Instructor in Medicine at Harvard Medical School in Boston, MA. She received her M.D. from the University of São Paulo in Brazil, where she also worked in a basic oncology laboratory and completed residency in Internal Medicine. After relocating to the U.S., she repeated her Internal Medicine residency at the University of Connecticut and completed a five-year clinical and research fellowship in adult nephrology in the joint Brigham and Women’s Hospital / Massachusetts General Hospital program. Impressed by how genetics revolutionized medicine and motivated to find missing diagnoses for kidney disease patients, she became interested in searching for genetic determinants of kidney disorders.

Brigham & Women’s Hospital in Boston, MA

Harvard Medical School

Lay Summary of the Project:

During the genetic revolution of the last two decades, important discoveries have revealed the major role of genetic factors in kidney function, development and disease. Humans have tens of thousands of genes, which are segments of DNA that guide how our bodies function. Hundreds of forms of chronic kidney disease have been shown to be caused by defects in single genes – including more than 60 genes for nephrotic syndrome (NS), a clinical condition in which the kidneys lose a large amount of protein. As genetic knowledge has transformed the understanding of kidney disease, we are moving to personalized, genetics-guided clinical kidney care. However, many patients with suspected genetic kidney disease still do not have a diagnosis, and the mechanisms by which some genetic factors cause disease are still obscure. In this setting, different genetic studies are needed, including one called allele-specific expression (ASE). An allele is a copy of a gene: for almost all of our genes, there are two copies (two alleles) – one that we received from our mother, and one received from our father. The DNA sequence of a gene is used to create mRNA, a molecule that serves as an intermediate for the subsequent production of a protein. By analyzing someone’s mRNA sequences, we can often identify specifically from which of the two gene copies (two alleles) the mRNA molecules originated from.

When performing ASE analysis, we calculate the number of mRNA molecules (collectively called “gene expression”) originating from each of the two alleles: if the number is the same, this is called balanced expression. However, if most of the mRNA comes from one specific allele, this is called “allele-specific expression.” ASE has already been shown to contribute to several illnesses, including autism, heart disease and cancer. For example, in a person who has one normal gene copy and one defective gene copy, if the expression is skewed towards the defective allele, this person may have more severe disease. From a kidney standpoint, a prior study by our group found that individuals with NS had ASE of NPHS1 – a gene responsible for the production of nephrin, a very important component of the kidney filter. However, ASE studies in human kidney disease are limited.

Goals and Significance: In this project, our goal is to identify occurrence of ASE in the kidney filtering units (glomeruli) of individuals from the Nephrotic Syndrome Study Network (NEPTUNE). We believe that discovering skewed expression of certain genes can help identify new genetic mechanisms contributing to kidney disease, urine protein loss and NS. To this end, we will search for ASE of genes known to cause NS, when mutated. We will then look for genes that have greater ASE in NEPTUNE participants, compared to healthy kidney samples. Next, we will search for which locations within the DNA are causing the imbalance in mRNA. Finally, we will overlap this with a database that shows which DNA regions are actively being used by each kidney cell type. This can allow us to pinpoint where in the kidney the ASE is happening. In summary, our study seeks to identify ASE occurring in kidneys of patients with significant urine protein loss (e.g., NS) and use this data to identify new pathways leading to kidney disease. We also aim to make this ASE information available to all researchers through an online portal, to contribute to more studies and, hopefully, to future clinical diagnostic and treatment strategies.

 

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