An international team of researchers led by Academician Yuan-Tsong Chen and Dr. Jeffery Yen, respectively Director and Research Fellow of the Institute of Biomedical Sciences at Academia Sinica have demonstrated that mutation of one gene can result in the manifestation of a diverse array of serious diseases in mice. For the first time, the group has found a direct link between one particular type of protein modification and common problems, such as hair loss and osteoporosis, an exciting first step to understanding the molecular mechanisms underlying these diseases. The study was published in the international scientific journal PLoS Genetics on June 10, 2010 (US Eastern Standard Time).

        The team, which included Dr. Monica Justice, a Professor at Baylor College of Medicine in Houston, found that defective “palmitoylation” resulted in the characteristics of several serious diseases being seen in the mice. Palmitoylation is a common protein modification that involves the addition of palmitate (a fatty acid) to proteins. Many soluble and integral membrane proteins have been shown to be palmitoylated, including signaling proteins, enzymes, scaffolding proteins, ion channels, cell adhesion molecules, and neuronal proteins. Despite the known functional importance of protein palmitoylation at the cellular and biochemical levels, its physiological role and its relevance to disease processes has not been clear.

        In the study defective palmitoylation caused hair loss; severe osteoporosis; cachexia, a wasting syndrome characterized by loss of weight, weakness and fatigue often seen in patients with chronic diseases such as cancer, AIDS or tuberculosis; and systemic amyloidosis, a deadly protein misfolding disease in which misfolded proteins destroy vital organs such as the heart, kidneys and liver. It also causes early death.

        The defective palmitoylation was caused by a mutation in the Zdhhc13 gene which codes for palmitoyl acyltransferase, the enzyme that catalyzes protein palmitoylation. The multi-organ/system failure of mice with mutated Zdhhc13 established a direct link between protein palmitoylation and the regulation of many important diverse physiological functions, and indicates that the absence of Zdhhc13 can result in profound disease pathologies.

         The mouse model developed by the team will be useful for further investigation of the mechanisms by which improper palmitoylation leads to diseases, including the identification of target proteins of ZDHHC13. The elucidation of these proteins would be an exciting first step to understanding the molecular mechanisms underlying human alopecia, osteoporosis and many neurodegenerative diseases caused by protein misfolding and amyloidosis.

        The research of Dr. Yuan-Tsong Chen and his team at the Institute of Biomedical Sciences is wide ranging, but he is most well-known for his pioneering work with rare genetic diseases. His previous research has included enzyme and gene therapy for Pompe disease, a fatal genetic muscle disorder, and the genetic and molecular mechanisms of Stevens-Johnson syndrome, a life-threatening skin disease. Dr. Chen’s search for a cure for Pompe disease was featured in the 2010 movie “Extraordinary Measures” starring Harrison Ford.

        The full article entitled “Mice with Alopecia, Osteoporosis and Systemic Amyloidosis due to Mutation in Zdhhc13, a Gene coding for Palmitoyl Acyltransferase” is available at the PLoS journal website at: http://www.plosgenetics.org/home.action.

        The full list of authors is: Amir N. Saleem, Yen-Hui Chen, Hwa Jin Baek, Ya-Wen Hsiao, Hong-Wen Huang, Hsiao-Jung Kao, Kai-Ming Liu, Li-Fen Shen, I-wen Song, Chen-Pei D. Tu, Jer-Yuarn Wu, Tateki Kikuchi, Monica J. Justice, Jeffrey J.Y. Yen, and Yuan-Tsong Chen.