Cell-cell adhesion is a fundamental prerequisite for the development of multicellular architecture and is facilitated by specific adhesion molecules. Cadherins, divided into several subfamilies, represent a major protein family acting as such adhesion molecules. FAT1 is a member of the cadherin family and plays an important role in actin dynamics and cell migration, and it regulates cell-cell interactions. The protein is expressed in various fetal epithelia and its expression peaks during embryonal development and diminishes in adult life. Recessive missense mutations in FAT1 have been associated with an isolated glomerulotubular nephropathy.

In a recent study published in Nature Communications, to which also scientists at the Institute of Human Genetics of the University Medical Center Göttingen contributed, researchers identified for the first time FAT1 gene variants as the underlying cause of a novel syndrome manifesting with eye malformations (coloboma) and kidney, skeletal and face anomalies. In their subsequent experiments in mouse and zebrafish models, the researchers investigated the functional effects of the mutations they had detected in five affected families and established that the loss of FAT1 protein function was associated with the development of coloboma in these models. They also showed for the first time that FAT1 is expressed in human primary retinal pigment epithelium cells, implicating a role of FAT1 in optic fissure fusion during embryonal eye development. The results of the study show that FAT1 is a gene wherein genetic variations have pleiotropic effects: biallelic missense mutations cause a non-syndromic glomerulotubular nephropathy, while homozygous frameshift mutations lead to a multisystem disorder.