An international research consortium led by the Universitat Autònoma de Barcelona (UAB), the CIBERER and the University of Wurzburg (Germany) has discovered a gene that can cause three totally different diseases, depending on how it is altered.
The researchers, using next-generation massive ultrasequencing techniques, have sequenced the over 20,000 genes of a Fanconi anaemia patient’s genome. By adopting this strategy they have succeeded in identifying pathogenic mutations responsible for this disease in the ERCC4 gene, which had already been linked to two other rare diseases: xeroderma pigmentosum and a type of progeria. The latter are characterised by heightened sensitivity to sunlight, susceptibility to skin cancer and, in the case of progeria, premature aging. Fanconi anaemia, on the other hand, is characterised by progressive anaemia, congenital malformations and a high risk of developing leukaemia and mouth tumours. The ERCC4 gene can therefore be responsible for three different diseases.
The researchers have shown that this gene is involved in two DNA repair mechanisms by which cells maintain the stability of the genome, in such a way that the balance between these two repair systems will determine which of the three diseases the patient will contract. “This is a rather exceptional case, since there are few precedents of a single gene being involved in two independent physiological mechanisms and causing three clinically different diseases”, points out UAB professor Dr Jordi Surrallés.
These findings, published today in the “American Journal of Human Genetics”, as well as improving the diagnosis and genetic characterisation of rare diseases, will allow new therapeutic strategies to be applied, like gene therapy or the selection of healthy, compatible embryos to cure siblings through umbilical cord transplants. The findings add to our knowledge of the two DNA repair mechanisms, which are so important for maintaining the stability of our genes and preventing cancer in the general population. In fact, the researchers point to the importance of going on to study this gene’s possible role in breast cancer and ovarian cancer.
Xeroderma pigmentosa is a rare condition passed down through families in which the skin and tissue covering the eye are extremely sensitive to ultraviolet light.
Xeroderma pigmentosum (XP) was first described in 1874 by Hebra and Kaposi. In 1882, Kaposi coined the term xeroderma pigmentosum for the condition, referring to its characteristic dry, pigmented skin. Xeroderma pigmentosum is a rare disorder transmitted in an autosomal recessive manner. It is characterized by photosensitivity, pigmentary changes, premature skin aging, and malignant tumor development. These manifestations are due to a cellular hypersensitivity to ultraviolet (UV) radiation resulting from a defect in DNA repair.
Xeroderma pigmentosa is an autosomal recessive disorder. It means you must have two copies of an abnormal gene in order for the disease or trait to develop.
Ultraviolet light - such as that found in sunlight - damages the genetic material (DNA) in skin cells. Normally, the body repairs this damage. But in persons with xeroderma pigmentosa, the body does not fix the damage. As a result, the skin gets very thin and patches of varying color (splotchy pigmentation) appear.
The condition also causes spidery blood vessels in the skin (telangiectasia) and skin cancer. Skin cancer often occurs before the child is 5 years old.
Sunburn that does not heal after just a little bit of sun exposure
Blistering after just a little bit of sun exposure
Spider-like blood vessels under the skin
Patches of discolored skin that get worse
Crusting of the skin
Scaling of the skin
Oozing raw skin surface
Discomfort when being in bright light (photophobia)
The study was co-directed by Dr. Jordi Surrallés, a UAB professor and researcher with the Biomedical Research Network on Rare Diseases (CIBERER) and Dr. Detlev Schindler, a professor at the University of Wurzburg. Participating in it were researchers from the VU University Medical Center (Netherlands), the Erasmus University of Rotterdam (Netherlands), Stony Brook University (New York, USA), the CNIO and the CIEMAT in Madrid, and the company Sistemas Genómicos, based in Valencia. The lead author, Massimo Bogliolo, is a researcher at the CIBERER and a lecturer at the UAB, attached to Dr. Surrallés group.
What Is Fanconi Anemia?
Fanconi anemia (fan-KO-nee uh-NEE-me-uh), or FA, is a rare, inherited blood disorder that leads to bone marrow failure. The disorder also is called Fanconi’s anemia.
FA prevents your bone marrow from making enough new blood cells for your body to work normally. FA also can cause your bone marrow to make many faulty blood cells. This can lead to serious health problems, such as leukemia (a type of blood cancer).
Although FA is a blood disorder, it also can affect many of your body’s organs, tissues, and systems. Children who inherit FA are at higher risk of being born with birth defects. FA also increases the risk of some cancers and other serious health problems.
FA is different from Fanconi syndrome. Fanconi syndrome affects the kidneys. It’s a rare and serious condition that mostly affects children.
Children who have Fanconi syndrome pass large amounts of key nutrients and chemicals through their urine. These children may have serious health and developmental problems.
Octavi López Coronado
Universitat Autonoma de Barcelona