How genetic mutations in a protein complex affect cilia, leading to ciliopathies
A group of scientists from IOR in Tübingen together with colleagues from Heidelberg University, and University College London has systematically investigated 23 genetic mutations in the IFT140 gene.
Ciliopathies are diseases caused by dysfunction of cilia, tiny hair-like structures on our cells that are necessary for cellular movement and sensing. The disease spectrum ranges from mild symptoms affecting single organs only to severe systemic disorders. A key protein involved in cilia function is IFT140, which is part of the transport system within the cilia.
Mutations in IFT140 can lead to conditions spanning the whole spectrum of ciliopathies, from mild vision impairment to severe multi-organ disorders, such as Mainzer-Saldino and Jeune syndrome. Therefore studying mutations in IFT140 provides valuable insights into the genetic and molecular mechanisms underlying the broad spectrum of diseases caused by cilia dysfunction.
A group of scientists from IOR in Tübingen together with colleagues from Heidelberg University, and University College London has systematically investigated 23 genetic mutations in the IFT140 gene to determine their effects on protein function and disease severity. The findings, published in the journal ‘Molecular & Cellular Proteomics’, reveal that while some mutations significantly weaken the ability of IFT140 to interact with other components of the ciliary transport system, they do not necessarily prevent cilia from forming. This suggests that the system has a high degree of built-in resilience. A key discovery is that IFT140 mutations often disrupt interactions with TULP3, another crucial protein responsible for transporting signaling molecules into cilia. In more than half of the mutations studied this interaction was disturbed, which may contribute to disease symptoms.
Beyond expanding our understanding of ciliopathies, this study has important implications for diagnosis and treatment. It helps to explain why individuals carrying mutations in the same gene may experience vastly different symptoms, making it a valuable resource for genetic counseling. Additionally, it challenges the traditional "all or nothing" view of genetic diseases by demonstrating that some mutations partially disrupt function rather than completely disabling it. This insight suggests a new therapeutic approach: instead of replacing the faulty gene, future treatments could focus on improving the remaining function of IFT140, potentially allowing for more targeted and effective interventions.
Here the link to the original publication: Ciliopathy-associated missense mutations in IFT140 are tolerated by the inherent resilience of the IFT machinery
by Tina Beyer, Gaurav D. Diwan, Tobias Leonhard, Katrin Dahlke, Franziska Klose, Isabel F. Stehle, Marian Seda, Sylvia Bolz, Franziska Woerz, Robert B. Russell, Dagan Jenkins, Marius Ueffing, Karsten Boldt
