Presented by David Chuang, PhD
Dr. Chuang's talk focused on MSUD research performed by his laboratory and colleagues.
Although MSUD was first reported about 46 years ago, Dr. Chang stated, "There is still no cure for MSUD, but progress has been made in biochemistry, molecular genetics, and in the treatment of the disease." Dr. Chuang attributes this achievement to the tremendous advances made in research over the last 15 years. His talk focused on several aspects of MSUD research.
One aspect is the biochemistry of MSUD which involves studying the interaction of the biomolecules which constitute the Branched-Chain a-keto Acid Dehydrogenase (BCKD) complex and their relationship to other cellular components. The BCKD complex plays a vital role in the catabolism of leucine, isoleucine and valine. It was quite exciting to hear that Dr. Chuang, along with his colleagues, had resolved the crystal structure of the branched-chain a-keto acid dehydrogenase. This is the first report of resolving the crystal structure of any human a-keto acid decarboxylase. The highlight is that, with this knowledge, researchers could now predict more confidently how certain mutations may interrupt the normal functioning of the BCKD complex and cause MSUD.
The molecular genetics (studying and identifying the genes which encode the BCKD complex) and the mutational analysis of MSUD are tasks that can be tedious when identifying new mutations that lead to MSUD. There are six different genes that encode for the BCKD complex; however, only 4 of them have been fully sequenced at the DNA level. To further complicate matters, the four genes are located on different chromosomes in the genome, and a mutation in any one of them has the potential to cause MSUD. As Dr. Chuang explained, mutational analysis is very important. To emphasize this, he listed several points:
- Identifies mutations for prenatal diagnosis of MSUD
- Sheds light on the association of a mutant allele with certain groups
- Facilitates the study of the biochemistry of MSUD
- Promotes the development of biochemical strategies which can be used to mitigate the disease
Dr. Chuang also commented that in order to use gene therapy, doctors first need to know which of the patient's genes is affected. But, as he informed the audience, "This is not as simple as it sounds."
Dr. Chuang discussed thiamine responsive MSUD. After several studies, his lab has observed a strong correlation between the thiamine-responsive phenotype and a subset of Type II MSUD (mutations in BCKD E2 component). This suggests that patients in this category are candidates for thiamine treatment.
The study of assembly defects involves utilizing biochemical strategies to determine how the proteins that constitute the BCKD are shaped and folded, as well as, how the proteins potentially interact. From his extensive studies with cell cultures, Dr. Chuang was able to conclude that the defects in protein folding and assembly, caused by certain MSUD mutations, can be partially reversed by specific chemical compounds. Dr. Chuang stressed that this is just the beginning, and these observations depend greatly upon the nature of the defect which causes MSUD.