Recent study offers new insights on a hereditary eye disease

On June 9, 2020, the team of Professor Guan Minxin from the School of Medicine, Institute of Genetics of Zhejiang University published the article titled as “PRICKLE3 linked to ATPase biogenesis manifested Leber’s hereditary optic neuropathy” in the Journal of Clinical Investigation.

In this study, the mutation of the X-linked nuclear modification gene PRICKLE3 was discovered for the first time and it was found to synergistically function with mitochondrial mutation, thus triggering Leber’s hereditary optic neuropathy (LHON). Their findings answered the long-time unsolved question of’gender bias’associated with this hereditary eye disease, which marks a milestone breakthrough in the research on pathogenic mechanism of mitochondrial disease LHON.

A systematic large-scale gene screening of more than 200 Han ethnic LHON families helped to the discovery of the X-linked gene PRICKLE3. A series of functional studies also revealed the synergy between mitochondrial gene 11778G>A mutation and X-linked nuclear modification gene mutation leading to the aggravation of the mitochondrial energy metabolism.

LHON is one of the most common maternal genetic diseases (female to male transmission), usually manifested as painless acute vision loss in both eyes, especially among young men aged 18-20. LHON is caused by genetic factors, environmental factors, or a combination of the two. MtDNA mutations are the main molecular basis of LHON, however its molecular pathogenic mechanism has not yet been fully clarified. In 1988, American professor Wallace first discovered that LHON is mainly caused by the lack of energy metabolism due to the mutations in three mitochondrial genes, m.11778G>A, m.14484T>C, and m.3460 G>A. The characteristics of penetrance and high incidence of males in different populations suggest that X-linked nuclear modification genes play a decisive role in the pathogenic mechanism of LHON. However, these genes have not been identified for thirty years.

Professor Guan has long been engaged in the research of molecular pathogenic mechanism and clinical translation of maternal genetic diseases. Since 2003, Professor Guan has conducted a systematic and comprehensive study on the pathogenic mechanism of LHON in the Chinese population, exploring new strategies for disease diagnosis and prevention. He collaborated with many domestic units to collect the largest LHON cohort in the world, mapped the mutation spectrum of mitochondrial genes in the Chinese population, identified multiple new mutation sites and conducted functional studies. In 2016, the important role of autosomal nuclear modification gene YARS2 in the pathogenesis of LHON was first discovered. Relevant achievements have published more than 40 original series of papers in international journals such as OPHTHALMOLOGY, HUMAN MOLECULAR GENETICS, IOVS, etc., and have obtained 6 national authorized patents, and won the second prize of National Science and Technology Progress Award in 2007.

As a medical scientist, in addition to publishing an original series of basic research papers (highly cited authors for six consecutive years), Professor Guan also actively writes popular science articles and clinical practice guidelines.

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