Craniofacial disease: Treacher Collins syndrome

A big question in Biology is how to get specificity from generality. Every cell has certain components that are essential for the life and function of the cell. For example, every cell has DNA which needs to be made into RNA and then to protein. Every cell has organelles like the nucleus and mitochondria. How do mutations in key components of every cell only cause disease in certain parts of the body?

One such example is Treacher Collins syndrome. Treacher Collins syndrome is a rare genetic disorders characterized by deformities in the facial structure. Typical features include downward slanting eyes, sunken cheekbones, small jaw, cleft palate and small or absent ears. Due to the physical deformities, many patients suffer from hearing loss, problems swallowing or breathing. Despite the many facial deformities, patients do not have mental retardation. In fact, a friend of mine who has Treacher Collins syndrome is working towards a PhD.

Since the symptoms of Treacher Collins syndrome are very specific and restricted to the face, you would expect the causal mutation to be in a face-specific gene. However, it is actually caused by mutations in TCOF1, POLR1C or POLR1D. These are genes involved in making ribosomal RNA. Ribosomal RNA are essential components of ribosomes. Ribosomes are molecular machines that are responsible for making all the proteins in the cell. Every cell has ribosomes and need ribosomes to survive. Hence as you can imagine, TCOF1, POLR1C and POLR1D are found in almost every cell in the body. Why then, do patients only show defects in the face when these genes are mutated?

A recent study has shed some light on how one of these genes TCOF1 can cause specificity. TCOF1 encodes a protein called Treacle. It has been known that Treacle works in the nucleoli, which are spots in the cell where ribosomes are made. Treacle has been shown to be involved in making ribosomal RNA as well as putting on modifications of the rRNA. When Treacle is broken, there are fewer functional ribosomes. One theory is that the cells which form the face are more sensitive to broken ribosomes and that is why patients have facial defects.

A large part of the face, including most of the bones and nerves, is formed by a type of cells called neural crest. The new study shows that when Treacle is not functional, cells that should become neural crest don't. Instead they become neurons. Why do they do that? Turns out that Treacle works with a complex of proteins to make proper ribosomes. The Treacle complex brings the RNA Pol I complex, ribosome maturation complex and rRNA modification complexes together. These complexes are responsible for making the RNA components of ribosomes, fold it in the right way, put on the right proteins and add the right modification marks.

The Treacle complex (red) needs to be ubiquitylated (Ub) to make normal ribosomes (green). Without Ub, ribosomes (blue) formed causes pluripotent stem cells to beoome neural progenitors instead of neural crest cells. As neural crest cells are involved in forming facial structures, this produces multiple facial defects in patients.

The Treacle complex itself needs to have a special mark, ubiquitylation, to be fully functional. Without ubiquitylation, or if the Treacle complex is otherwise broken, ribosomes can still form, but they behave differently from the usual ribosomes. Using a technique called ribosome profiling, the scientists looked at what proteins ribosomes are making. Normal ribosomes don't make proteins for specifying neural fate (brain, spinal cord) until neural crest specification (face) is finished. Ribosomes formed from a broken Treacle complex make neural precursor proteins earlier than usual. This turns stem cells into neurons earlier than they should. Because of this, stem cells don't get a chance to become neural crest. The lack of neural crest cells could explain why patients have facial defects.

This is the first explanation of how Treacle can cause neural crest/ face-specific defects. This is probably just one of the ways how Treacle mutations cause Treacher-Collins syndrome. Other ways will await further discovery.

For more information on Treacher-Collins syndrome and treatment options, please check out the following links:
FACES
Medicine Net