Protein Imbalance Linked to Rare Developmental Disorder

According to a recent study from the University of Lausanne, serious intellectual impairments can result from both an excess or a shortage of a single protein. The finding provides important new information for the early identification of a rare developmental condition.

A group of scientists led by Alexandre Reymond, a professor at the University of Lausanne (UNIL) Faculty of Biology and Medicine (FBM) and expert in human genetics at the Center for Integrative Genomics (CIG), has made an important advancement in the identification of a rare genetic condition.

The authors demonstrate for the first time that the so-called AFF3 protein is harmful to development when it accumulates and is deficient. The study, which was published in Genome Medicine, builds on the study that the scientists conducted in 2021 when they identified the KINSSHIP syndrome, which is caused by mutations in the AFF3 gene and causes intellectual disabilities, kidney anomalies, and bone deformities in affected children

Discovery of the Genetic Cause of KINSSHIP Syndrome

KINSSHIP syndrome affects around thirty people globally. As a result, the disease is still little understood, and there are few recorded occurrences, which makes it difficult to diagnose the condition early and accurately.

In our previous study we demonstrated that this pathology resulted from an abnormal accumulation of the AFF3 protein. Meanwhile, available genetic data from individuals of the general population suggested that a lack of this same protein could be similarly deleterious.”

Dr Sissy Bassani, Study Lead Author and Postdoctoral Researcher, University of Lausanne

Large Genome Database Points Researchers to a New Hypothesis

The geneticists developed their hypothesis using gnomAD, a database including genome sequences from several hundred thousand unrelated people. Through a thorough analysis of the available data, the scientists discovered that loss-of-function mutations in the AFF3 gene are uncommon, which suggests that they are probably deleterious.

This suggests that this gene is important and that the organism would suffer if it were to become extinct. To verify their hypothesis, the authors looked for people with only one copy of the gene rather than the two typically found in the human genome.

Working with researchers from nine countries in Europe and North America, they found 21 people with this aberration. While their symptoms were not as severe as those of people with KINSSHIP syndrome, they were all identical.

Experiments Reveal the Developmental Impact of AFF3 Gene Mutations

The researchers employed a variety of experimental systems, including patient cells, mice, and zebrafish, to show that both insufficient and excessive amounts of AFF3 consumption are harmful. Significant developmental abnormalities were found in the fish embryos produced when the amount of protein in zebrafish eggs was either increased or decreased.

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.”

Alexandre Reymond, Professor, Department of Biology and Medicine and Human Genetics, Center for Integrative Genomics, University of Lausanne

Impact for Prenatal Diagnostics

Testing for AAF3 mutations during fetal development could improve the early detection of these gene defects, making the authors’ results a significant step toward diagnosing this rare disorder.

Journal reference:

Bassani, S., et al. (2024) Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles. Genome Medicine.


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