Rare gene variants linked to missing, extra and baby teeth, and to how birds lost theirs

Rare variants in a gene involved in early development have been linked to a striking range of dental differences in people, including missing teeth, unusual tooth shapes and sizes, and teeth present at birth. By studying changes in the same gene in mice and chickens, an international team of researchers, including scientists from King’s College London, has also uncovered clues to how differences in tooth number and shape evolved across species, including how birds may have lost their teeth. The study, published in Proceedings of the National Academy of Sciences, connects a single developmental gene to outcomes that can point in opposite directions depending on where in the jaw it acts.

The gene in question is C2CD3. In a cohort of 24 patients, the researchers linked a variety of changes in tooth number, shape and size to changes in this gene. When the team removed C2CD3 in mice, the animals mimicked many of the dental changes seen in the patients, highlighting how the gene helps control tooth development across different species. Professor Abigail Tucker, Professor of Development & Evolution at King’s College London, said: “This paper was a great team effort, combining analysis of patients with tooth defects with an understanding of the mechanisms leading to these defects in mice. It was exciting to see that, like the patients, the mice had both extra and missing teeth in different parts of the jaw.”

C2CD3 helps build tiny structures inside cells called primary cilia, which act like antennae, allowing cells to receive and process signals that guide development. In the developing mouth, the researchers found that disrupting the gene altered the activity of a key developmental signalling pathway called Sonic hedgehog, or SHH, which helps determine where teeth form and how they develop. This placed the gene’s dental effects within a defined signalling network rather than an unexplained correlation.

The most revealing detail was spatial. In mice with disrupted C2CD3, SHH activity increased in parts of the developing upper jaw but decreased in the lower jaw. That opposing pattern provides a possible explanation for how changes to the same gene can lead to different outcomes, including additional teeth in some locations and missing teeth in others. “We were able to show that a change in C2CD3 function could have both tooth-enhancing and tooth-repressing effects dependent on the position in the jaw,” said Tucker. “So one gene could control very different dental outcomes. These findings help us understand what controls differences in our teeth, while also giving us a window into how tooth development changed over the course of vertebrate evolution.”

The research also reaches into evolutionary history. Although birds do not naturally have teeth, the researchers found tooth-like structures in embryos of the talpid2 chicken mutant, which carries a variant of C2CD3. These embryos can develop tooth-like structures, making them a useful model for investigating how the biological processes involved in tooth formation work. The embryos showed increased SHH activity in both the upper and lower jaws, suggesting that changing this developmental signalling system can influence the ability to form teeth even in a lineage that no longer grows them.

Taken together, the findings suggest that birds lost their teeth during evolution not because they lost all the biological machinery needed to grow them, but because the developmental processes that form teeth became switched off or suppressed. That interpretation frames tooth loss in birds as a change in developmental regulation rather than the disappearance of the underlying tooth-forming apparatus, and it identifies C2CD3 and the SHH pathway as components of the machinery involved.

For patients, the study offers a mechanistic account of rare dental abnormalities rather than an immediate treatment. The researchers say the work will help explain why tooth defects occur, helping to refine treatments for those with complex dental problems, and that it reveals how C2CD3 helps regulate tooth formation across vertebrate species. Because the human findings come from a small group of 24 patients and the mechanistic evidence comes from mouse and chicken models, the results describe associations and developmental mechanisms in model systems rather than proven clinical outcomes. Even so, tying a cilia-building gene to a signalling pathway that positions and shapes teeth gives clinicians and developmental biologists a shared framework for understanding a spectrum of rare dental conditions.

The broader significance lies in the convergence of three lines of evidence: human genetics, mouse developmental biology and avian embryology, all pointing at the same gene and the same pathway. A variant that in people produces missing teeth, extra teeth or teeth present at birth produces matching patterns when engineered in mice, and in chickens it coaxes tooth-like structures out of jaws that normally make none. The study thus links the clinic to the evolutionary record through a single molecular lever, showing how one gene, acting through primary cilia and the Sonic hedgehog pathway, can shape both the smiles of individual patients and the history of vertebrate teeth.

Subject of Research: Rare C2CD3 gene variants linked to human tooth defects and the evolutionary loss of teeth in birds

Article Title: Rare gene variants linked to dental differences that shape our smiles

Article References: Rare gene variants linked to dental differences that shape our smiles. Original publication (Bibliographic details unavailable.)

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Keywords: C2CD3, primary cilia, Sonic hedgehog pathway, tooth development, dental abnormalities, developmental genetics, evolutionary biology, bird tooth loss, talpid2 chicken mutant, King's College London, PNAS, vertebrate evolution