WHEN A SINGLE GENE WHISPERS, MEDICINE MUST LISTEN CLOSELY: WILSON’S DISEASE

 

A single base change in a single gene can completely abrogate the function of the protein it codes for. Fortunately, our genome is manufactured with backups: A second copy of the gene, an allele, that can code for the right protein. However, what if both the inherited alleles of the gene are mutated? That becomes a rare and unfortunate occurrence leading to a devastating disease, and sometimes even costing us a life. 

Samuel Alexander Kinnear Wilson

Wilson’s disease, first described by Kinnear Wilson in 1912 as “progressive lenticular degeneration” is a life-altering disease caused due to the presence of two abnormal copies of the ATPase copper-transporting β (ATP7B) gene located on chromosome 13 (Autosomal Recessive Inheritance). The ATP7B gene codes for a transmembrane ATPase-dependent copper transporter protein called Wilson’s Disease protein or ATP7B which is essential for the excretion of copper through the bile.

The copper in our diet is absorbed through the stomach and the duodenum and transported to the liver, which is the organ responsible for copper homeostasis, via the portal vein. The membranes of the hepatocytes that face the sinusoidal blood in the liver receive the copper facilitated by the Copper Transporter 1 (CTR1) protein. The received copper is transported to ATP7B present in the trans-Golgi networks by a molecular chaperone ATOX1 through a copper-dependent protein-protein interaction. ATP7B in turn facilitates the transport of copper through the trans-Golgi compartments and into the holo-ceruloplasmin (copper-containing glycoproteins synthesized in the liver that help in transporting copper throughout the body). Whenever copper concentrations and accumulations increase, ATP7B loads them onto vesicles to export into the bile where ATP7B directly interacts with another protein, MURR1 for biliary excretion of copper. 

Copper Transport by ATP7B protein

About one in 40,000 to 50,000 people are affected by Wilson’s Disease, which suggests that one in 180 to 300 people could be carriers of a single mutated allele of the gene according to the Hardy-Weinburg equilibrium under the assumption of 100% penetration of the disease. However, studies from France and Italy suggest that the genetic prevalence of the disease might be three to four times higher than the actual clinical prevalence of the disease suggesting a less than 100% penetrance. The prevalence of this disease is even higher in regions where first-cousin marriages are common since the manifestation of the disease requires the inheritance of mutated ATP7B gene from both the parents leading to the presence of two abnormal copies in the child.

The key to surviving this disease is early diagnosis. The earlier the diagnosis, the better the prognosis. A confirmed diagnosis of Wilson’s Disease is typically done after clinical manifestations of any one of the three are observed: Hepatic, Neurological, or Psychiatric symptoms. Hepatic impairment is often observed in early childhood or adolescence, while neurological and psychiatric symptoms typically manifest later, The manifestation timeline of these symptoms varies among patients. All this while, before the clinical manifestation of symptoms the disease is causing harm asymptomatically. Though genetic screening diagnosis capabilities of laboratories have tremendously improved in the past decades, clinical and biochemical tests such as the appearance of Kay Feisher’s rings in the eyes, ceruloplasmin levels in the blood, and amount of copper present in the urine over 24 hours remain the gold standard of Wilson’s Disease diagnosis. While genetic testing to detect mutations in the ATP7B gene is available for confirmation, barriers still exist to its transformation from laboratories to hospitals, mainly because of genetic heterogeneity. Over 800 mutations are observed in the ATP7B gene, some of which have unknown significance, making universal diagnosis a challenge. Other barriers include the cost and accessibility of the genetic screening methods, and the lack of awareness among the general public to get screened often finding out they have the disease too late after organ damage.

Mutations in the ATP7B gene

When Wilson’s disease is diagnosed early, it becomes manageable with lifelong oral pharmacotherapy consisting of copper chelators such as D-penicillamine and trientine. Zinc is also prescribed as first-line treatment to asymptomatic patients which inhibits intestinal copper absorption. Asymptomatic patients are expected to not show any symptoms after treatment and have survival rates similar to the general public. Liver Transplants are recommended for patients with severe hepatic impairment. Although these options seem like a lifesaver, the patient’s quality of life declines due to adverse side effects such as kidney damage, bone marrow issues, gastritis, lupus-like symptoms, and skin conditions like lichen planus and blistering rashes. Hence, molecular targeted therapies that can restore the function of ATP7B are an absolute requirement to combat this disease and are actively being developed by Life Science Researchers such as peptides derived from heat shock proteins that can restore localization of ATP7B, and phase I/II clinical trials for gene therapy using Adeno-associated viruses. The development of these approaches into clinically meaningful therapies is yet to unfold. 

Wilson’s Disease may be rare, but its impact is devastating when left undiagnosed. Every missed diagnosis is a life altered, a future rewritten, or ended with a full stop by preventable complications. Despite advancements in research, too many patients continue to suffer due to late detection and limited treatment options. Awareness is the first step—both among healthcare professionals and the general public. Routine screening in high-risk individuals, improved access to genetic testing, and continued investment in molecular therapies are not luxuries but necessities. Until we move beyond managing symptoms to restoring ATP7B function, Wilson’s Disease will remain a ticking time bomb for those who carry its silent mutation. The science is evolving—what remains is the urgency to turn breakthroughs into reality.

This article is written in tribute to Nikita Naiyar, former chairperson of St Teresa’s College, Ernakulam, Kerala, India, and a beloved daughter. Nikita fought bravely against Wilson’s Disease, enduring two liver transplants until her last breath at the age of 21 on 25th January 2025. 

Nikita Naiyar

Nikita’s parents could only discover she had Wilson’s Disease when she was 8 years old—by then, she already needed a liver transplant. She was transplanted with her mother’s liver. She and her parents expected to face complications only at the age of 30. Unfortunately, she had to face them much earlier. 13 years after her first liver transplant, she developed Portal Vein Thrombosis (PVT) which led her liver to fail again. Nikita with an unwavering spirit, went through another liver transplant. Nikita was a warrior at heart and fought until the last minute, but due to rare complications of a retransplant she finally had to let go. Even in her final moments, Nikita made a beautiful mark on this world. She asked her doctors to donate whatever they could from her body. She left two people with the gift of sight. The world lost a wonderful soul only because of a single gene mutation.

Nikita was the only daughter of her proud parents. Her parents watched her enter the OR for the last time with a smile. They find comfort in knowing that she lived a meaningful life, embracing every moment she could. Her charm, kindness, strength, and unwavering spirit touched everyone who knew her. We at Scioverleaf dedicate this article as a painful reminder that the research conducted by scientists worldwide—and by us as future scientists—does not just impact molecules and genes, but actual lives. For us, it was a single mutation; for her, it was her fate. Hence, When a Single Gene Whispers, Medicine Must Listen Closely.

REFERENCES:

Wungjiranirun M, Sharzehi K. Wilson’s Disease. Semin Neurol. 2023;43(4):626-33. doi:10.1055/s-0043-1771465.

IMAGE CREDITS: 

1. Cover Image: https://www.barraquer.com/en/news/wilson-disease-eyes

2. Samuel Alexander Kinnear Wilson: https://www.sciencedirect.com/science/article/pii/S0967586805002833

3. Copper Transport by ATP7B protein: Reference Article

4. Mutations in the ATP7B gene: https://www.researchgate.net/figure/Schematic-representation-of-ATP7B-mutations-detected-in-the-present-study-The-novel_fig4_49741270

5. Nikita Naiyar: Social media platforms