Scheduled Times According to Time Zones:
United States West Coat: 9:00AM
United States East Coast: 12:00PM
Israel: 6:00 PM
Saudi Arabia & Turkey: 7:00PM
Korea & Japan: 1:00AM (4/15)
Introducing Mokol Lek:
Monkol received an undergraduate degree in Engineering (Computer Engineering) in 2000 at the University of New South Wales (UNSW) and then worked for IBM for 3.5 years. He returned to UNSW and completed undergraduate degrees in Science (Physiology) and Engineering (Bioinformatics) and received the University Medal in 2007. He completed his PhD (Medicine) at the University of Sydney in 2012. Monkol did his post-doctoral training in Daniel MacArthur’s lab based at Massachusetts General Hospital, Harvard Medical School and the Broad Institute.
Monkol has a strong passion for rare muscle disease research as a patient with Limb Girdle Muscular dystrophy (LGMD2G). During his time in the Broad Institute, he lead the exome/genome analysis of MYOSEQ (European cohort of >1000 LGMD patients) and SeqNMD (an international consortium of undiagnosed rare muscle diseases) which has resulted in novel disease gene discovery. He is currently an Assistant Professor and Research Group Leader at The Yale School of Medicine's Department of Genetics.
Dr. Marjan Huizing
Dr. Huizing investigates rare human genetic disorders and associated intracellular processes in order to gain insight into the changes in molecular function that underlie various genetic metabolic disorders, with the hope of developing treatments for these illnesses. Her research focuses on disorders of sialic acid metabolism and of lysosome-related organelles.
Sialic acid is a negatively charged sugar localized at the end of glycoconjugate chains on glycoproteins and glycolipids. These chains are present on the cell surface and are crucial for many biological processes, including cell adhesion and signal transduction. Sialic acid synthesis is tightly regulated; defects in this pathway cause a variety of disorders, including hereditary inclusion body myopathy (HIBM), sialuria, infantile sialic acid storage disease (ISSD), and Salla disease.
HIBM is caused by mutations in the gene encoding the key enzyme in sialic acid synthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase, which in turn leads to sialic acid deficiency. Without adequate supplies of sialic acid, progressive muscle degeneration (or myopathy) sets in. Dr. Huizing has demonstrated that muscle ?-dystroglycan, an integral component of the muscle transmembrane dystrophin-glycoprotein complex, is low in sialic acid in HIBM patients. Based on this observation, they developed a mouse model mimicking HIBM. These mice die of unexpected glomerular disease due to hyposialylation of kidney glycoproteins, leading to severe proteinuria and hematuria. Oral administration of the sialic acid precursor N-acetyl-mannosamine (ManNAc) partially rescues the kidney defect, allowing the mutant mice to survive. Dr. Huizing is currently evaluating the use of ManNAc not only as a treatment for HIBM, but also for renal disorders involving glomerular disease-associated proteinuria and hematuria.
Dr. Huizing also studies other sialic acid-related diseases, including sialuria, a progressive disease in which patients produce excess sialic acid. Symptoms can include developmental delay, coarse features, and liver enlargement. Sialuria appears to be due to a single mutation that causes a change in the three-dimensional structure of the active site of the UDP-GlcNAc 2-epimerase/ManNAc kinase enzyme. Dr. Huizing demonstrated that elimination of the single mutant allele using a synthetic small interfering RNA (siRNA) rescued the abnormal phenotype in cultured cells from sialuria patients. In ISSD and Salla disease, other sialic acid-related conditions, a transport malfunction causes sialic acid to accumulate in lysosomes. Dr. Huizing is evaluating possible steps to alleviate this sialic acid accumulation in cultured cells from ISSD and Salla patients.
Dr. Huizing is also investigating the causes of and potential treatments for disorders of lysosome-related organelles (LROs), including Hermansky-Pudlak syndrome (HPS), Chediak-Higashi syndrome, and Griscelli syndrome. A rare inherited disorder that has been identified in about 400 people worldwide, HPS is mainly characterized by decreased pigmentation (ocular or cutaneous albinism) and a lack of platelet dense bodies that causes bleeding problems. The disease can lead to prolonged bleeding and poor function of the lungs and intestine; fatal pulmonary fibrosis is a possible complication. An ongoing clinical trial at NHGRI is testing the drug pirfenidone as a potential HPS treatment for symptoms associated with pulmonary fibrosis.
Dr. Huizing continues to search for novel genes causing LRO disorders, with the hope of better understanding the biological causes of these conditions. She played a major role in identifying six distinct genetic subgroups of HPS patients by cataloging relevant clinical and genetic characteristics. To study the effects of LRO-related gene mutations, Dr. Huizing is performing fluorescent protein expression studies using patients' cells in order to examine defective intracellular trafficking. These results will be instructive for elucidating the complex vesicular transport processes that are involved in the biogenesis of LROs.