Thus, while the increase in genetic testing has provided clinicians and researchers with more genetic data than ever before, we now find ourselves with the pressing need to classify these variants in order to provide actionable information for patients.
One such gene of interest to researchers and clinicians is the transmembrane protein TMEM67 (also called MKS3 for Meckel syndrome type 3). This gene is known for encoding the meckelin protein, which is a key regulator of cilia function (Liu et al., 2021). Notably, pathogenic mutations in theTMEM67 gene have been found to play a central role in ciliopathies such as Meckel Syndrome, COACH Syndrome, and Joubert Syndrome.
Ciliopathies are a collection of heterogeneous diseases categorized/grouped by their abnormal formation or function of cilia. Cilia are hair-like organelles that protrude from the surface of nearly every cell type and are essential for many signaling pathways and processes associated with development and disease. Consequently, when they are dysfunctional, these small structures cause severely debilitating to deadly disorders — for instance, Meckel Syndrome has a 100% mortality rate either in utero or shortly after birth (Liu et al., 2021).
While TMEM67 is known to be associated with these catastrophic disorders, the majority of their variants currently have unknown clinical significance (52.1% according to ClinVar) (Lange et al., 2022). In light of this need, many researchers (such as Oliver Blacque and his lab) are turning to alternative animal models such as zebrafish, Drosophila, and C. elegans to evaluate these variants. These models are attractive to researchers as they offer the invaluable advantages of being relatively inexpensive and fast in vivo platforms for preclinical studies and therapeutics discovery [Figure 2].