Contrary to previous belief, a group of researchers from the University of Basel and University Hospital Basel have found that carriers of single-allele genetic defects, who were thought to be asymptomatic, can also endure severe illnesses. This revelation implies that the incidence of rare genetic diseases could be higher than we previously assumed. Focusing on a recessive hereditary immunological disorder, the study revealed that single-allele defects can hinder the immune system, possibly leading to adult-onset diseases and atypical symptoms.
Defects in genetic material often lead to rare diseases. When children inherit one malfunctioning gene from a parent, they are generally asymptomatic “carriers” – at least, that’s what was previously believed.
This traditional understanding is being challenged by researchers from the University of Basel and University Hospital Basel. Their research suggests that these carriers may also be victims of severe, potentially life-threatening conditions. As a result, it’s likely that such rare hereditary diseases are more frequent than initially thought.
Humans typically have two copies – called “alleles” – of most genes, as they receive one set of chromosomes from each parent. Many rare genetic diseases manifest only if both alleles of a gene are defective, which is known as a “recessive” hereditary disease. If only one allele is flawed, the other can often compensate, preventing any symptoms from occurring.
Numerous immunological disorders fall under the category of recessive hereditary diseases. These are caused by mutations in an estimated 2,500 to 5,000 immune-related genes and are characterized by increased susceptibility to infections or autoimmunity, where the body’s immune system mistakenly attacks itself.
Professor Mike Recher’s team at the University of Basel and University Hospital Basel used a recessive hereditary disease as a case study to show that even a single defective allele can pose a risk of impaired immune system function. “Past assumptions have often overlooked such cases, believing that defects only cause problems if present in both alleles,” Recher says. “Yet, carriers can indeed face life-threatening diseases, often appearing in adulthood with unconventional symptoms.” The study, which involved researchers led by Dr. Hiroyuki Yamamoto from Japan’s National Institute of Infectious Diseases (NIID), has been published in The Journal of Allergy and Clinical Immunology.
The researchers detailed mutations in the genetic blueprint for an enzyme that is vital for antibody and T-cell diversity. Mutations in both alleles of this LIG4 gene disrupt the body’s immune response, leading to a higher risk of severe infections from a young age.
It was previously thought that carriers with only one defective LIG4 allele were asymptomatic. However, Recher and his team have now identified numerous instances where such individuals have displayed severe symptoms somewhat akin to the original inherited disease. “Having only one functional LIG4 gene seems to be insufficient in these cases,” the immunologist states.
Despite the thousands of genes involved in the human immune system, not enough is known about the many single-allele mutations and their role in a person’s lifetime immune response. “Our research, along with other recent studies, indicates that these defects may be the root cause of previously unidentified immune disorders more often than we thought.”
“We believe many rare recessive diseases may have more common, yet unidentified, counterparts that are associated with unusual symptoms, tend to occur later in life, and exhibit a different inheritance pattern,” says Recher. However, there will still be healthy carriers. “Environmental factors such as infections and epigenetics also contribute.”
Recher emphasizes the importance of incorporating these new findings into diagnostics. “Understanding the issue at a molecular level can present highly targeted treatment options that often have fewer side effects and tackle not just the symptoms, but the root cause of the problem.”
Reference: “Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency” by Annaïse J. Jauch, Olivier Bignucolo, Sayuri Seki, Marie Ghraichy, Ottavia M. Delmonte, Valentin von Niederhäusern, Rebecca Higgins, Adhideb Ghosh, Masako Nishizawa, Mariko Tanaka, Adrian Baldrich, Julius Köppen, Julia R. Hirsiger, Robin Hupfer, Stephan Ehl, Anne Rensing-Ehl, Helmut Hopfer, Spasenija Savic Prince, Stephen R. Daley, Florian A. Marquardsen and Mike Recher, 31 March 2023, Journal of Allergy and Clinical Immunology.
DOI: 10.1016/j.jaci.2023.03.022
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Frequently Asked Questions (FAQs) about Rare Genetic Diseases
What discovery did the researchers from the University of Basel and University Hospital Basel make?
The researchers found that carriers of single-allele genetic defects, who were traditionally considered asymptomatic, can also suffer from severe illnesses. This suggests that the occurrence of rare genetic diseases might be more common than previously assumed.
What do we mean by single-allele genetic defects?
Every human has two copies of most genes, known as “alleles.” They receive one set of chromosomes from each parent. Many rare genetic diseases only manifest if both alleles of a gene carry a defect. However, if only one allele is flawed, the other can often compensate, resulting in no symptoms. This is known as a single-allele genetic defect.
What are the implications of this research for individuals with a single-allele genetic defect?
This research implies that carriers of a single-allele genetic defect can also be victims of severe, potentially life-threatening conditions, often appearing in adulthood with unconventional symptoms. This challenges the previous belief that carriers were largely asymptomatic.
Does this study suggest that rare recessive diseases are more common than previously thought?
Yes, according to the researchers’ findings, rare recessive diseases might be more frequent than previously thought. Their research suggests that many such diseases might have more common, yet unidentified counterparts, associated with unusual symptoms and a different inheritance pattern.
How can this research impact future diagnostics and treatment options?
This research emphasizes the importance of understanding genetic defects at a molecular level. Such understanding can lead to highly targeted treatment options that often have fewer side effects, addressing not just the symptoms but also the root cause of the condition.
More about Rare Genetic Diseases
- University of Basel Research
- University Hospital Basel Studies
- Journal of Allergy and Clinical Immunology Publication
- National Institute of Infectious Diseases (NIID)
- Information about Genetic Disorders
- Insights on Recessive Hereditary Diseases
6 comments
Makes u think how much we don’t know yet about our own bodies! Scary and exciting at the same time. Hope this can help many people in future.
this is massive! means we gotta rethink our whole understanding of rare genetic diseases. Puts a new spin on things, eh?
i can’t believe i’ve just read this. My brother’s a carrier for a genetic defect, and we always assumed he was safe, but this changes everything 🙁
Wow, thats big news. Who’d have thought so-called “rare” diseases might not be so rare after all.
This is a groundbreaking study. Reinforces the importance of continuous genetic research in improving healthcare. Great work!
Fascinating stuff! The world of genetics is always full of surprises. Amazing research from the Basel team. Kudos to them.