Duke-NUS Associate Professor David Silver co-led two Nature Genetics published studies which showed that mutations in the protein Mfsd2a causes impaired brain development in humans. Mfsd2a is the transporter in the brain for a special type of fat called lysophosphatidylcholines (LPCs) -- composed of essential fatty acids like omega-3. These studies show, for the first time, the crucial role of these fats in human brain growth and function.
The difference between a brain with a normal Mfsd2a gene and a brain with a mutated Mfsd2a gene.
In the first study, two families in Libya and Egypt with Mfsd2a mutations were identified with severely reduced brain size, or microcephaly. Their mutations eliminated Mfsd2a's ability to transport LPCs, which meant not enough LPCs were absorbed by the brain. In these families, children affected by these mutations died between one and six years of age. The study not only establishes a link between the transport of LPCs by Mfsd2a and human brain growth and function, it is also the first time a genetic disease has been related to LPC transport in humans. The research was co-led by senior author Professor Joseph Gleeson from Rockefeller University.
In a second, separate study, a family in North Pakistan was found to have another type of mutation in the Mfsd2a gene which reduced its transport activity. The individuals with this mutation also had microcephaly, but in this case it was not lethal. However, they did have intellectual disabilities, impaired control of their limbs, and absent speech. Like the first study, findings are proof of the importance of LPCs in brain development and function. The research was co-led by senior author Professor Andrew H. Crosby from Exeter University.
In 2014, Dr. Silver published a landmark study in Nature which served as a basis for these two studies. He and his team discovered that Mfsd2a is the transporter for LPCs. Prior to this breakthrough, LPCs were known to be found at high concentrations in our blood but their function was a mystery. Dr. Silver's team showed that mice genetically engineered without Mfsd2a failed to transport LPCs into their brains - which resulted in microcephaly.
"Our work confirms the essential role of LPCs in brain development and function in humans, and indicates that brain uptake of LPCs during foetal development and in adult life is important," said Dr. Silver, co-lead on both studies, based in the Cardiovascular and Metabolic Disorders Programme at Duke-NUS.