Danish researchers have identified a completely new and extremely rare genetic mutation that causes reduced brain size in a family with 10 cases of the mutation.
In recent years, the whole world became aware of primary microcephaly after an outbreak of Zika virus that resulted in many children in South America being born with reduced head size, reduced brain volume and intellectual disability.
However, microcephaly is not solely linked to Zika virus. It is also a genetic disorder, and researchers from the University of Copenhagen have now helped to identify the genetic mutation that caused 10 cases of primary microcephaly in a family from Pakistan.
The discovery provides deeper insight into what goes wrong in the brain during fetal development to make children have heads and brains that are significantly smaller than normal at birth.
“This is an extremely rare mutation that we have only found in this family, in which 10 people have microcephaly. Although the mutation is very rare, the discovery helps to shed more light on the processes involved when the brain does not develop normally,” explains a researcher behind the study, Lars Allan Larsen, Professor, Medical Genetics Program, Faculty of Health and Medical Sciences, University of Copenhagen.
Lars Allan Larsen and his colleague, Søren Tvorup Christensen, Professor of Cell Biology and Physiology, Faculty of Science, University of Copenhagen have published their research in Nature Communications.
Marriages between close family members increases the risk of genetic disorders
Microcephaly has many causes, including genetic mutations and infection with various microbes during pregnancy, including Zika virus, Toxoplasma gondii, herpesvirus, varicella zoster virus and HIV.
Lars Allan Larsen and colleagues investigated the genetic background for the fact that 10 people in a large family with marriage between close relatives had severe microcephaly.
Lars Allan Larsen says that genetic studies of rare families like this enable researchers to identify disease-related genes that are very difficult to identify by other means.
Some people carry genes for a given disease in one of their two chromosomes, but since these people often have a healthy gene as well, the pathogenic mutation is not expressed.
However, when two people in the same family carry the same disease gene and have children, the child risks getting two copies of the pathogenic gene, and then things go wrong.
“Some populations have strong traditions of marriage between cousins, but the downside may be that recessive disease genes are expressed because children inherit them from both parents. Normally, getting one of these genes from one parent does not matter. However, as we observed, if you get the gene from both parents, this can end up as microcephaly,” explains Lars Allan Larsen.
The researchers took blood samples from the intermarried family and then identified the mutated gene that caused the many cases of microcephaly.
However, the researchers were surprised because the mutation turned out to influence two very different processes, which in combination have not previously been described in the development of primary microcephaly.
The genes that produce microcephaly are often involved in the function of centrosomes, a small organelle in cells that ensures normal cell division. If the genes that control the rate and organization of cell division malfunction, the brain becomes smaller than normal as a result of defects in the formation of new neurons.
“The gene we identified encodes a protein that is involved in processing RNA molecules, which are involved in protein synthesis, and also involved in the primary cilia, which are cellular antenna that coordinate signalling between the cells during brain development. No previous studies have focused on the fact that combining these mechanisms could cause microcephaly. Nevertheless, this makes good sense, because the accumulated effect slows the rate of both cell division and the formation of new neurons,” says Søren Tvorup Christensen.
Mutations in zebrafish cause reduced brain size
After the researchers identified the genetic mutation that caused the many cases of microcephaly in the family studied, they examined how the gene functions in both stem cell cultures and zebrafish.
The researchers observed that male and female zebrafish, each with one copy of the specific genetic mutation, often had larvae with much smaller brains.
The researchers tried to discover whether other researchers had studied this genetic mutation, but all evidence indicates that the family studied is genetically unique.
“Researchers worldwide can upload their genetic results to an international database. This enables us to determine whether any other researchers have found the same genetic mutation. However, in recent years, we are the only ones who have found this genetic mutation associated with microcephaly. This suggests that the genetic mutation is extremely rare and may only be present in this one family,” explains Lars Allan Larsen.
Improving insight into brain development
Lars Allan Larsen and Søren Tvorup Christensen explain that, although the research results are only directly relevant to the family investigated, their study can improve the insight of other researchers into the processes that influence the formation of the brain during fetal development.
Many of the genes that various research groups have identified as being involved in developing microcephaly paint an overall picture of the mechanisms that ensure that the brain achieves the right size.
The genes involved largely control the process by which stem cells differentiate into neurons and how the nerve cells replicate so that one cell becomes two and then becomes an entire brain over time.
The new research results also suggest that the mutation in the family studied may affect some of the same processes by which Zika virus causes microcephaly. According to Søren Tvorup Christensen, this provides completely new perspectives in understanding how environmental factors can cause the brain to be underdeveloped and can cause cognitive dysfunction.
“This is a very controlled process, and many things can go wrong, resulting in the brain not developing as it should. We have obtained better insight into this now, and it has great research value. In addition, the affected family can use the information directly in family planning. It is now possible to identify who is carrying the mutation and who is not. This information can be used for giving the family genetic counselling,” says Lars Allan Larsen.