Human beings are extremely fragile. A single gene mutation is enough to cause faulty brain connections. Dr. Deborah Morris-Rosendahl and her team at the Freiburg Medical School are investigating genetic cephalic disorders which are collectively referred to as lissencephaly. The scientists offer clinical diagnostics and investigate the causes of the disease. This may well provide further insights into how billions of neurones are able to find their correct place in healthy brains.
A smooth brain (which is the definition of lissencephaly) does not really sound that bad – at least at first sight. However, the lack of brain folds in the cortex that make the outer brain layer look like a walnut, leads to severe neurological impairments, including mental disorders, motor impairments, increased risk of epilepsy and a drastically reduced life expectancy. Patients suffering from lissencephaly are fully dependent on help and care. “Lissencephaly is an awful disease which mainly affects children,” said the biologist Deborah Morris-Rosendahl from the Institute of Human Genetics at the University of Freiburg. There is no cure for this disease. Nevertheless, it is important to understand its causes. First, because information about defective brain formation provides information on how the human brain develops normally. And second, because any knowledge helps parents of children with lissencephaly.
"Knowledge of the genetic errors that lead to lissencephaly enables us to offer parents prenatal diagnostics and determine whether children yet to be born might also be at risk of contracting lissencephaly," said Morris-Rosendahl. More than 12 genes associated with lissencephaly are known. Different mutations in the DNA sequences lead to differently pronounced malformations of the cortex. Encephalic symptoms often occur in combination with others, for example a small brain, a small cerebellum or a defective corpus callosum, which connects the two brain hemispheres. One of our major tasks is to associate the malformations on an MRI image with the genotype of the patient," said Morris-Rosendahl. "On the basis of MRI images, we would be able to predict the mutated genes."
The biologist and her team are not only interested in diagnostics. They are also interested in how lissencephaly develops. The development of the brain can be roughly divided into three phases: first, the precursor cells of the neurones need to propagate in order to produce sufficient tissue. Then the neurones migrate from inside the brain to the outside where they build the outer layer known as the cortex. They then have to find their place in the correct sublayers and contact other cells. It has long been assumed that lissencephaly resulted exclusively from the lack of neuronal migration. But this is not the case. Four known lissencephaly genes code for proteins that are important for the cytoskeleton. The lack or malfunction of these genes leads to the defective formation of the microtubuli. The neurones lose their flexibility and do not reach their destined location.
"We now know that some of the genes involved in the first phase of brain development are very important," said Morris-Rosendahl. "In addition, the processes of the neurones are also affected, thereby leading to defects in the establishment of contacts with other neurones during the third phase of neuronal development." An excellent example of defects in the first phase of neuronal development is the mutations in the gene PAFAH1B1 (also known as LIS1) which codes for a microtubuli-associated protein that has an effect on the mode of action of microtubuli, and hence on the migration of cells and on the cytoskeleton that turns into a mitosis spindle during the division of the neuronal precursor cells. The mitotic spindle helps to divide the duplicated chromosomes to the two daughter cells and it organises the division of the nucleus. If this process is defective, then the neuronal precursor cells divide on the wrong level, which leads to fewer neurones and a slightly smaller brain.
The more we learn about the effect of the genes that lead to lissencephaly, the better our understanding about the development of the normal brain,” said Morris-Rosendahl. “For us, this is equally as important as improving clinical diagnostics.” The Freiburg scientists are thus very keen to receive samples from patients who do not carry a mutation in the known genes. They will then look for other genes that might be mutated. They have already discovered four interesting chromosome regions with genes that are potentially related to lissencephaly. If they are able to identify the genes, then they hope to be able to clarify the function of the corresponding genes in the healthy brain. This knowledge might also benefit parents of lissencephaly patients, because it helps to make differential and prenatal diagnostics even more accurate.
Further information:Dr. rer. nat. Deborah Morris-RosendahlInstitute of Human GeneticsFreiburg Medical SchoolBreisacher Str. 33 D-79106 Freiburg i. Br.Tel.: +49-(0)761/270-7027 (-7028)Fax: +49-(0)761/270-7041E-mail: deborah.morris-rosendahl(at)uniklinik-freiburg.de