The NPHS2 gene provides instructions for creating a protein involved in the normal operation of the kidneys, organs responsible for filtering waste from the blood. Understanding this gene helps clarify its connection to kidney health.
The Role of NPHS2 in Kidney Function
The NPHS2 gene directs the production of a protein known as podocin, which is found primarily in the kidneys. Within the kidneys, filtering units called glomeruli contain specialized cells called podocytes. Podocin is situated at the surface of these podocytes, specifically in the area between two podocytes, forming a structure called the slit diaphragm.
The slit diaphragm functions as a filtration barrier. Its purpose is to retain proteins within the bloodstream while allowing smaller molecules, such as salts and waste products, to pass through and be excreted in urine. Podocin helps bring other proteins necessary for a functional slit diaphragm to the podocyte cell surface and participates in podocyte cell signaling.
NPHS2 Mutations and Kidney Disease
When the NPHS2 gene undergoes mutations, the instructions for making podocin are faulty, leading to a defective or absent podocin protein. This malfunction compromises the integrity of the slit diaphragm, the kidney’s delicate filter. Consequently, large amounts of protein can leak from the blood into the urine, a condition known as proteinuria.
This protein leakage is a hallmark of specific kidney conditions, notably Steroid-Resistant Nephrotic Syndrome (SRNS) and a form of Focal Segmental Glomerulosclerosis (FSGS). NPHS2-related kidney disease is inherited in an autosomal recessive pattern, meaning a child must inherit one mutated copy of the NPHS2 gene from each parent to develop the condition.
Patients with homozygous or compound heterozygous NPHS2 mutations present with SRNS before the age of six years and often experience rapid progression to end-stage kidney disease. NPHS2 mutations are the most frequent cause of congenital nephrotic syndrome, a kidney disorder beginning in infancy.
Diagnosing NPHS2-Related Conditions
Diagnosis begins when clinical signs suggest kidney issues, such as swelling and foamy urine. These symptoms prompt laboratory tests to check for high levels of protein in the urine, a primary indicator of kidney filtration problems. Blood tests may also reveal low protein levels in the blood.
Because these symptoms can arise from various causes, a definitive diagnosis for an NPHS2-related condition requires genetic testing to examine the NPHS2 gene for specific mutations that confirm the underlying cause of the kidney disease. A kidney biopsy, which involves examining a small tissue sample under a microscope, may also be performed to assess kidney damage, often showing changes like focal segmental glomerulosclerosis.
Managing NPHS2-Associated Nephrotic Syndrome
NPHS2-associated nephrotic syndrome is termed “steroid-resistant” because it does not respond to standard steroid therapies, which are the first-line treatment for other forms of nephrotic syndrome. Management focuses on supportive care aimed at slowing the progression of kidney damage and addressing symptoms.
Medications to reduce proteinuria, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), are prescribed. These medications lessen the amount of protein lost in the urine and help control blood pressure. Diuretics are used to manage fluid retention and reduce swelling. Dietary adjustments, including sodium restriction, are recommended to control edema. While there is currently no cure, ongoing research continues to explore more targeted therapies for this condition.