A recent study carried out at the University of Lausanne reveals that both excess and deficiency of the same protein can lead to severe intellectual impairment. The discovery opens up vital prospects for the early diagnosis of a rare developmental disorder.
A team of scientists led by Alexandre Reymond, an expert in human genetics at the Centre intégratif de génomique (CIG) and Professor at the Faculty of Biology and Medicine (FBM) at the University of Lausanne (UNIL), has produced a major breakthrough in the detection of a rare genetic disease. For the first time, the authors have shown that both excess and deficiency of a protein called AFF3 have adverse effects on embryonic development. Their study, published in Genome Medicine, follows the discovery, in 2021, of the KINSSHIP syndrome, due to mutations in the AFF3 gene and leading to intellectual deficiencies, a risk of epilepsy, kidney and bone malformations in affected children.
Discovery of the genetic cause of KINSSHIP syndrome
KINSSHIP syndrome is a rare disease, affecting around 30 people worldwide, making early and accurate diagnosis difficult. In our previous study, we demonstrated that this pathology resulted from an abnormal accumulation of the AFF3 protein. However, the genetic data available from a large number of different individuals suggested that a lack of this same protein could be just as harmful", explains Dr. Sissy Bassani, a post-doctoral fellow in Reymond’s team and first author of the current study.
Genomic database leads scientists to new hypothesis
The geneticists formulated their hypothesis using gnomAD , a database containing genome sequences from several hundred thousand unrelated individuals. Examining the information available on variants in the AFF3 gene, the scientists found that loss-of-function mutations in this gene are very rare, suggesting that these mutations are probably deleterious. This means that this gene is crucial, and its loss of function could have serious consequences for the organism. To test their hypothesis, the authors looked for individuals carrying a single copy of the gene, instead of the two copies normally present in human DNA. Working with researchers in nine European and North American countries, they identified 21 patients with this anomaly. Their symptoms are similar to those of KINSSHIP syndrome, but less severe.
Experiments reveal the impact of AFF3 gene mutations on development
To demonstrate that both too little and too much AFF3 are harmful, the scientists used several different experimental systems: cells from patients, mice and zebrafish. Both decreasing and artificially increasing the amount of the protein in zebrafish eggs resulted in major developmental defects in the fish embryos. These results confirm that a precise amount of AFF3 is crucial for proper embryonic development, and that mutations affecting its function and/or dosage cause severe malformations", concludes Prof. Reymond.
Impact on prenatal diagnosis
These results represent an important advance in the diagnosis of this rare developmental disorder. Screening forAFF3 mutations during fetal development could enable early detection of these genetic anomalies.
Bassani, S., et al. Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles. Genome Medicine (2024). https://doi.org/10.1186/s13073’024 -01339-y
