On the Trail of a Rare Disease

06/30/2025

An international research team led by Würzburg has identified another gene whose functional failure leads to Fanconi anaemia.

Graphically altered representation of the FA core complex, consisting of eight proteins with FAAP100/FANCX in the centre, in its function as a mediator for the repair of certain types of DNA damage. (Image: Reinhard Kalb / Uni Würzburg)

Fanconi anaemia (FA) is a rare hereditary disease whose symptoms include congenital malformations and progressive bone marrow failure. It also leads to an increased risk of cancer, particularly cancers of the blood and mucous membranes.

The disease is triggered by mutations in one of 22 known genes, the so-called FANC genes. The Institute of Human Genetics at Julius-Maximilians-Universität Würzburg (JMU) has now identified another of these genes. The researchers have published their findings in The Journal of Clinical Investigation.

Repair of DNA Damage Disrupted

Every day, tens of thousands of DNA damages occur in each of our body cells that need to be repaired. This usually happens extremely reliably and efficiently. In patients with Fanconi anaemia, however, certain DNA repair mechanisms, particularly for the repair of chemical cross-links of the DNA double strand, are disrupted. The result: faulty repair, which can lead to malfunctions or even cell death.

In a study, researchers from Würzburg and the USA coordinated by Professor Detlev Schindler describes that a genetic variant of the FAAP100 gene leads to FA-typical developmental disorders. "The variant impairs the function of an important protein complex that is involved in the repair of DNA damage," says Dr Reinhard Kalb, who heads the Soma Cell Genetics research group at the Institute of Human Genetics.

Experiments in cell and animal models have shown that the discovered variant, or a lack of FAAP100, leads to chromosomal and genomic instability. "At the molecular level, this is because FAAP100 normally performs an important scaffolding function in the FA core complex, which is lost as a result of the mutation, meaning that certain DNA repair functions can no longer be carried out," Dr Reinhard Kalb explains further.

As a result of these findings, the FAAP100 gene has now been included in the list of disease-causing FANC genes under the name FANCX as the twenty-third gene.

Relevance for Patients

Knowledge about the genetic cause of the disease is important for diagnosis and therefore for sound genetic counselling and the necessary medical care.

It is also necessary to exclude Fanconi anaemia in patients with certain suspected symptoms before starting treatment in order to avoid a treatment-related risk.

In addition to further research into the link between FA and hereditary cancers, the researchers are also focussing on another possible consequence: The severity of malformations in FANCX-related Fanconi anaemia suggests that it could play a role in unexplained miscarriages. This option should be investigated further in the future.

Cooperation Partners and Funding

In addition to researchers from Würzburg, colleagues from the USA were also involved in the work. These included working groups at the Laboratory of Genetics and Genomics at the National Institute on Aging in Baltimore, the Department of Biochemistry and Molecular Biology at the Miller School of Medicine at the University of Miami and the Genomics Core and Cancer Genomics Unit at the National Human Genome Research Institute, National Institutes of Health in Bethesda, Maryland.

The work in Würzburg was financially supported by the Schroeder-Kurth Fund and the German Federal Ministry of Education and Research.

Publication

Julia Kuehl, Yutong Xue, Fenghua Yuan, Ramanagouda Ramanagoudr-Bhojappa, Simone Pickel, Reinhard Kalb, Settara C. Chandrasekharappa, Weidong Wang, Yanbin Zhang, and Detlev Schindler: " Genetic inactivation of FAAP100 causes Fanconi anemia due to disruption of the monoubiquitin ligase core complex" in The Journal of Clinical Investigation. DOI: 10.1172/JCI187323