Genetic basis - PLN is linked to mutations in the NPHS1 gene, which encodes nephrin, a key protein in the kidney’s filtration barrier at the slit diaphragm between podocytes. Mutations in NPHS1 disrupt nephrin function, impairing the glomerular filtration barrier and allowing proteins to leak into the urine. NPHS1 mutations are commonly found in combination with KIRREL2 gene mutations, both contributing to PLN risk. The inheritance pattern is complex, likely autosomal recessive with variable penetrance, meaning genetic and environmental factors both influence disease development.

Pathophysiology - Nephrin deficiency leads to a compromised filtration barrier in the glomerulus, allowing loss of plasma proteins in urine (proteinuria). Consequent low blood albumin levels cause edema and fluid accumulation in tissues. Progressive loss of protein and kidney damage leads to kidney failure over time.

Complications - Clinical signs develop in middle-aged to older dogs (commonly 4-8 years). Symptoms include muscle wasting, weight loss, vomiting, diarrhea, increased thirst and urination, and fluid accumulation (edema and ascites). Secondary complications include hypertension, thrombosis, and eventual kidney failure. The disease often leads to poor prognosis and euthanasia in advanced cases.

Why This Matters to Breeders and Vets - For breeders, knowing NPHS1 mutation status helps prevent producing dogs with debilitating kidney disease, improving breed health and longevity. For veterinarians, understanding genetic risks helps in early diagnosis, management, and advising owners on expectations and care. Awareness of the complex, multigenic nature supports better breeding strategies and informed clinical care.