Cell ‘antennae’ hyperlink autism, congenital coronary heart illness
Repressing each of the seven genes one at a time in retinal pigment epithelial cells significantly reduced the percentage of cells sporting cilia. For six of those genes, cilia were shorter than usual. The same thing happened in neural progenitor cells when the team suppressed TAOK1 and KMT2E, two high-confidence autism-linked genes that have not been directly shown to be involved in cilia.
Reducing the expression of TAOK1 in the embryos of Xenopus tropicalis, a species of frog, impaired cilia formation and the frogs developed smaller forebrains and hearts than usual.
T
he results show that TAOK1 is “certainly important for heart development,” says Bruce Gelb, dean of child health research at the Icahn School of Medicine at Mt. Sinai, who was not involved in the work. But a smaller heart isn’t necessarily the same as CHD, he says, and the team should follow up with work in mice to see if clearer CHD phenotypes emerge.
Gelb co-led a 2015 study and another in 2017 that pointed to chromatin-modifying (or gene-expression regulating) genes as the intersection between autism and CHD. Chromatin regulators can also affect tubulin, the building block of microtubules, which are the central structure of cilia, according to a 2023 paper by Willsey’s team. In fact, the genes that Willsey’s January preprint linked to cilia are chromatin regulators.
“So, we think that there may be more to this chromatin regulation convergence than necessarily just gene expression changes, and that also may be a part of this cilia story,” she says.
A mystery remains: How do cilia disruptions contribute to autism?
“Ultimately, the critical question is whether changes in ciliary number and structure—and the resulting ciliary dysfunction—play a role in manifesting autistic-like features in model organisms,” Mustafa Sahin, professor of neurology at Harvard Medical School, wrote in an email to The Transmitter. Sahin was not involved in the new study but co-authored a 2022 review paper on the growing evidence for cilia defects in various neurodevelopmental disorders. “Unraveling this connection could be considered the ‘holy grail’ in cilia-related autism research,” he said.
