WEHI PhD Completion Seminar hosted by Professor Seth Masters

Dhanya Lakshmi Narayanan

PhD Student – Masters Laboratory – Hudson Institute of Medical Research

Partial loss-of-function variants in HMGCS1 cause a novel prenylopathy with myositis

Online presentation

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Including Q&A session

Prenylation is a process in which a lipid group is attached to a protein after it is synthesised. This process is essential for the protein’s localisation within the cell and for its activity. More than 300 proteins undergo prenylation, including the Rab and Rho small GTPases, which act as cellular switches. Prenylation depends on the isoprenoid lipids GGPP and FPP, which are products of the mevalonate pathway, an essential cellular pathway.

Genetic changes in mevalonate pathway genes, such as MVK and PMVK, can lead to defective prenylation and cause rare inherited immune disorders. These disorders belong to a growing family of inflammatory diseases known as ‘prenylopathies’.

We identified patients with recurrent inflammation, muscle inflammation and rare changes in both copies of the gene HMGCS1. This gene encodes the first enzyme of the mevalonate pathway. Using structural modelling, biochemical characterisation of the recombinant protein and cellular models, we examined how these variants affect protein function. Patient peripheral blood cells showed defective prenylation. The THP-1 cellular model showed inflammation mediated by pyrin. We define a novel prenylopathy caused by partial loss of HMGCS1 function.

Dhanya is a clinical geneticist, and her research focuses on monogenic autoinflammatory diseases and the functional characterisation of genetic variants. As a clinician-scientist, she is interested in translational research that bridges genomic discovery and disease biology to improve diagnosis and treatment for patients with rare inflammatory disorders. 

All welcome!