A Northwestern Medicine-led study has identified mutations in the gene CEP76 as a new cause of ciliopathies, shedding light on a complex group of disorders that affect multiple body systems, according to a study published in Science Advances.
Ciliopathies, a group of genetic disorders, are caused by defects in the structure or function of cilia, tiny hair-like organelles found on nearly all cells in the body. These cilia act as sensory and signaling hubs, playing critical roles in development, tissue maintenance and physiological processes. When they malfunction, they disrupt cellular signaling and transport, leading to widespread effects across multiple organ systems.
“For hundreds of years, we thought cilia weren’t doing anything important,” said Erica Davis, PhD, professor of Pediatrics and of Cell and Developmental Biology, who was the senior author of the study. “As it turns out, they’re so critical for development and homeostasis because this is how cells talk to each other during early development, during regenerative processes and how they sense their extracellular environment. If the cilia are not working, many things can go wrong.”
In the study, investigators discovered variants in CEP76 in eight unrelated individuals who presented with a range of symptoms, including neurodevelopmental delays, vision problems and other multisystemic issues.
Using patient-derived cells and zebrafish models, Davis and her collaborators observed defective cilium formation, shortened cilia and disrupted architecture at the transition zone — an essential gateway for molecular traffic in and out of the cilium. These defects were linked to impaired protein transport along the cilium.
Next, using proteomics to map CEP76’s interaction network, investigators found known partners CCP110 and CEP97, and new interaction partners ALMS1 (the genetic cause for Alström Syndrome) and LUZP1, a new candidate ciliopathy gene.
“CEP76 was not previously associated with any human condition,” said Kamal Khan, PhD, a postdoctoral associate in the Davis laboratory and first author of the study. “We demonstrated in both patient cells and zebrafish that when CEP76 is absent, cilia formation is disrupted, and the transport within the cilia is impaired.”
Improved scientific understanding of the genetic underpinnings of ciliopathies offers hope for families affected by these rare and often debilitating conditions, Davis said.
“By understanding the specific jobs of each protein and identifying others with similar functions, we can better interpret disease mechanisms and predict which individuals might have related genetic causes,” said Davis, who is also the Ann Marie and Francis Klocke, MD Research Scholar at Ann & Robert H. Lurie Children’s Hospital of Chicago. “Then we can begin to think about therapeutic targeting of similar genes and proteins that carry out similar jobs.”
Building on these findings, Davis said she and her laboratory are planning to study why the same genetic variants can manifest differently in each child and identify potential treatment targets.
“Something that’s fascinated me about ciliopathies for two decades is what makes affected people look different from each other? Why do their diseases progress differently? Why might parents look at their two affected kids with the same genetic cause and see that they’re completely different? We can tackle this from a genetic standpoint by looking at other variations in the genome that might be influencing these differences,” Davis said.
The study was supported by the Henry Brent Chair in Innovative Pediatric Ophthalmology Research, The SickKids Ophthalmology Research Fund, Canadian Institutes of Health Research FRN 156154, as well as U.S. National Institutes of Health grants NINDS R35 NS105078, NHGRI U01 HG0011758, R01 DK072301 and R01 HD042601.
