Researchers have discovered a gene that can cause three totally different diseases, depending on how it is altered: Fanconi anemia, xeroderma pigmentosum, or a type of progeria. They add that the gene could also be involved in breast and ovarian cancer.

Using whole-exome and Sanger sequencing, the researchers—led by the Universitat Autònoma de Barcelona, the CIBERER, and the University of Wurzburg—sequenced the DNA of unclassified Fanconi anemia individuals. They identified biallelic germline mutations responsible for this disease in the ERCC4 (XPF) gene, a structure-specific nuclease-encoding gene that had already been linked to two other rare diseases: xeroderma pigmentosum and a type of progeria called segmental XFE progeroid syndrome.

Xeroderma pigmentosum and this type of progeria are characterized by heightened sensitivity to sunlight, susceptibility to skin cancer and, in the case of progeria, premature aging. Fanconi anemia, on the other hand, is characterized by progressive bone marrow failure, congenital malformations, and a predisposition to cancer—particularly a high risk of developing leukemia and mouth tumors. The ERCC4 gene can therefore be responsible for three different diseases, the scientists say.

The researchers demonstrated 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 Barcelona professor Jordi Surrallés, Ph.D.

The team notes that these findings will help improve the diagnosis and genetic characterization of rare diseases, and also 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 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.

The findings were published yesterday in the American Journal of Human Genetics, in a paper titled “Mutations in ERCC4, Encoding the DNA-Repair Endonuclease XPF, Cause Fanconi Anemia”.

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