Researchers at the University of East Anglia have solved an 80-year-old medical mystery regarding the cause of kidney damage in children that resulted in numerous deaths during the 1930s and 1940s. Those affected by this condition are unable to metabolize vitamin D properly, causing calcium to accumulate in the blood, leading to kidney damage and kidney stones. This situation resulted in a wave of child fatalities in the 1930s and 1940s, following the fortification of foods such as milk, bread, grains, and margarine with vitamin D in an attempt to eradicate rickets in children.
Recent studies have revealed that the condition, now known as hypercalcemia in children type 1, is caused by a genetic mutation. However, intriguingly, around 10% of patients exhibiting symptoms do not have a genetic mutation. The lead researcher, Dr. Darryl Green from the Norwich Medical School at the University of East Anglia, stated, "This really puzzled us. We wanted to know exactly why these 10% are affected by this condition without the genetic mutation that has been identified as its cause."
The mystery began in the early 20th century when over 80% of children in industrial Europe and North America suffered from rickets, which caused bone pain, stunted growth, and soft, weak, and deformed bones. The discovery that sunlight prevented rickets led to the fortification of foods with vitamin D, which eliminated the disease by the 1930s. However, a vitamin D toxicity outbreak in infants led to a ban on this fortification in many European countries by the 1950s.
Dr. Green revealed, "In 2011, researchers found that some individuals are born with a mutation in the CYP24A1 gene, meaning they cannot metabolize vitamin D correctly. This results in calcium buildup in the blood, leading to kidney stones and kidney damage, which can be fatal in children. This was why vitamin D-fortified food in the '30s caused toxicity in some individuals."
He continued, "Today, some individuals are unaware they have a CYP24A1 mutation until they reach adulthood, often after years of recurrent kidney stones and other problems. In most cases, these patients are tested and found to have the CYP24A1 mutation and the disorder now known as hypercalcemia in children type 1, or HCINF1. However, about 10% of suspected HCINF1 patients do not exhibit a clear CYP24A1 mutation and continue to face lifelong issues without proper diagnosis."
To explore the reason for this, researchers at the University of East Anglia collaborated with colleagues at Norfolk and Norwich University Hospital, Croydon University Hospital, and the Royal Hospital for Children in Glasgow, studying data from 47 patients. They utilized a combination of next-generation genetic sequencing and computational modeling to analyze blood samples from these 10% perplexing patients.
PhD student Nicole Poole conducted a comprehensive genetic analysis of several patient blood samples and found that the physical form of the CYP24A1 gene in these patients clearly exhibiting hypercalcemia in children type 1 (HCINF1) was abnormal. In other words, the study discovered that patients with the condition but lacking a mutation in the CYP24A1 gene actually have a deformed CYP24A1 gene that produces the same effect.
Dr. Green explained, "This tells us that the shape of genes is important in gene regulation – this is why some individuals coexist with HCINF1 but without a definitive diagnosis." He added, "On a broader scale related to genetics and health, we know that genes must have the correct sequence to produce the right protein, but with an additional layer of complexity, we now understand that genes must also have the correct physical shape."
This discovery appears to have broad applicability across genetics and health in general. Researchers are now planning to investigate the role of gene shapes in other disorders such as cancer. The full findings have been published in the journal Bone and Mineral Research.
