Improved diagnostics

The worst is the uncertainty. When parents realise that their child is not developing in line with his or her age and lags behind children of the same age, they want to know one thing above all: what does our child lack? Is there a name and a diagnosis for these developmental conspicuities, and how can we best help our child? Ulrike Nuber is aware of the desire for a precise diagnosis of a developmental disorder as the professor for stem cell and development biology at TU Darmstadt is also a doctor and worked in the field of genetic counselling for a while. Her wish has always been to understand how illnesses arise, what implications they have and how they can best be treated – notably brain diseases in children.

Nuber, who was professor at the Stem Cell Center at Lund University in Sweden prior to her move to TU Darmstadt, is interested in the Coffin-Siris syndrome besides other paediatric brain diseases. This is a complex developmental disorder with various symptoms. The syndrome is caused by spontaneous genetic changes in a certain group of genes in the germ line of one parent or during early embryonic development. As such, the Coffin-Siris syndrome occurs at random and can affect anyone. Although the disorder is considered to be rare, many doctors believe that there are far more persons affected whose symptoms are not attributed to the syndrome. This might also be due to the fact that it is unclear as to which structural changes can occur in the brain and thus ought to be visible on an MRT scan.

Among the genetic changes that cause Coffin-Siris syndrome are mutations in the so-called SMARCB1 gene. Mutations in this gene also predispose for aggressive brain tumours in children and it is unclear in detail as to how such disparate clinical outcomes can arise. Nuber and her team member Dr Alina Filatova therefore wanted to find out what happens when the activity of this gene is reduced in brain stem cells. Is brain development disturbed or do brain tumours arise? Their experiments showed that mice do not develop tumours but exhibit marked changes in brain development. It is already visible with the naked eye that the animals’ brain is much too small and has conspicuous midline defects. In many mice, for example, the commissures connecting the two halves of the brain are underdeveloped or missing completely because the nerve fibres do not cross over to the opposite side. As such, many animals have no corpus callosum, the largest nerve tract in the brain of humans and mice. Moreover, many animals show pathological changes in the cerebellum and in the middle of the forebrain. In addition, the structure responsible for the production of brain fluid is too large.

The syndrome that bears the name of its discoverers, the American paediatrician Grange Coffin and the radiologist Evelyn Siris, stands for a general delay in development, a reduction in intelligence and reduced speech capability. The persons affected also have physical conspicuities. They are small, have dense eyebrows, a broad nasal bridge, low-set ears, a broad mouth and characteristic changes of the finger and toe end joints. Many persons affected also suffer from epilepsy and have eye or heart problems or other organic symptoms.

“When we saw the brain abnormalities in the mice, the next obvious question was if these structural changes can be seen on MRT scans of affected persons and why so little is known about it”, Nuber says. “Are there no such changes or have they simply been overlooked because doctors do not know which structural details to search for when analysing MRT scans?”.

Thereupon, Nuber asked the human geneticist Professor Dagmar Wieczorek and the paediatric radiologist Dr Jörg Schaper from Düsseldorf University Hospital to take another look at the MRT scans of affected persons. Wieczorek numbers among the leading experts in the field of the Coffin-Siris syndrome worldwide and contacted a human geneticist at Hamburg University Hospital as well as colleagues in Poland and Holland. Detailed analyses then revealed that individuals with Coffin-Siris syndrome demonstrate a similar spectrum of structural changes. The extent to which this is the case was previously unknown.

“The mouse model was important for letting us see and recognise this spectrum in the affected persons”, Nuber says. “Our findings have now provided doctors with an exact picture of what is possible. That is key additional knowledge for diagnostics”. Nuber expects the syndrome to be diagnosed in the future also via such structural brain changes. “Perhaps our findings will lead to the syndrome being considered more often in case of respective structural changes and then genetically confirmed.” Nuber, who sees herself as a genuine team player, was able to publish the results together with her colleagues in the respected open access journal “Nature Communications”. Admittedly, the findings from mouse models cannot always be translated so well to humans as in this case. This is why the group headed by Ulrike Nuber is also working on stem cell-based human disease models.

Which function does the protein product of the SMARCB1 gene have, the activity of which was reduced in the brain stem cells? The protein is part of a complex that makes the DNA accessible so that genes can be scanned. Genes that are occupied by so-called nucleosomes are inaccessible and cannot be read. The complex, which the SMARCB1 protein is part of, puts the nucleosomes away and clears the path to the genes. If the complex is defective or missing, the genetic programme cannot be correctly read and implemented, ultimately leading to the symptoms of the Coffin-Siris syndrome or to a predisposition for brain tumours. To date, little is known as to which genes can no longer be correctly read due to such a change.

Nuber sees the mice also as an important animal model for testing potential therapeutic approaches. One approach could be to correct the nerve cell defects. “Perhaps we can succeed in restoring the contacts between the nerve cells connecting the two hemispheres or in counteracting the consequences of too few nerve cells.” The stem cell researcher and doctor is grateful for the basic funding and personnel resources provided by TU Darmstadt. “Many projects are initially explorative and cannot be funded via external resources at that stage or take longer than the three years covered by standard external funding”, Nuber says. “Our mouse model for the Coffin-Siris syndrome is such a project. I am therefore delighted that TU Darmstadt makes projects of this kind possible. Research needs such free space.”