A recent study conducted at the University of Lausanne has revealed that both an excess and a deficiency of the AFF3 protein can lead to severe intellectual impairment. This discovery holds significant potential for the early diagnosis of a rare developmental disorder, known as KINSSHIP syndrome.
Key Findings
A team led by Alexandre Reymond, a human genetics expert at the Centre intégratif de génomique (CIG) and a Professor at the Faculty of Biology and Medicine (FBM) at the University of Lausanne (UNIL), has made a crucial breakthrough in detecting a rare genetic disease. The study, published in Genome Medicine, demonstrates for the first time that both overabundance and insufficiency of the AFF3 protein adversely impact embryonic development. This follows their 2021 discovery of KINSSHIP syndrome, which is linked to mutations in the AFF3 gene and results in intellectual deficiencies, epilepsy risk, and kidney and bone malformations in affected children.
KINSSHIP Syndrome and AFF3 Protein
KINSSHIP syndrome is an extremely rare disease, affecting approximately 30 individuals globally, complicating early and accurate diagnosis. Previously, the team showed that KINSSHIP syndrome was caused by an abnormal accumulation of the AFF3 protein. However, new genetic data suggested that a deficiency in this protein could be equally detrimental.
Hypothesis Formulation and Testing
Using the gnomAD database, which contains genome sequences from hundreds of thousands of unrelated individuals, the researchers found that loss-of-function mutations in the AFF3 gene are very rare, indicating their likely deleterious nature. This insight led the team to hypothesize that the gene is crucial and that its loss of function could have serious consequences.
Identification of Affected Individuals
Collaborating with researchers from nine European and North American countries, the team identified 21 patients who carried a single copy of the AFF3 gene instead of the typical two. These individuals exhibited symptoms similar to those of KINSSHIP syndrome, though less severe.
Experimental Confirmation
To confirm their findings, the researchers conducted experiments using patient cells, mice, and zebrafish. In zebrafish embryos, both the reduction and artificial increase of AFF3 protein levels caused significant developmental defects. These experiments underscored the importance of a precise amount of AFF3 for proper embryonic development, with mutations affecting its function or dosage leading to severe malformations.
Implications for Prenatal Diagnosis
This study represents a major advance in diagnosing KINSSHIP syndrome. Screening for AFF3 mutations during fetal development could facilitate the early detection of these genetic anomalies, potentially improving outcomes for affected individuals.
The University of Lausanne’s study on AFF3 protein levels opens new avenues for early diagnosis and better understanding of KINSSHIP syndrome. This research underscores the critical balance required in protein levels for normal development and highlights the potential for early intervention in managing this rare disorder.