STARD9 identified as causal gene for divergent familial dyslipidemias via lysosomal cholesterol trafficking

Researchers have posted a preprint to bioRxiv proposing STARD9 — a kinesin motor protein with a START domain that binds cholesterol to govern lysosomal positioning — as a causal gene for divergent familial dyslipidemias and premature atherosclerosis.

The preprint reports that rare variants in STARD9 segregate with autosomal dominant hypercholesterolaemia and premature coronary disease in affected families, while common variants in the same gene associate with reduced high-density lipoprotein (HDL) cholesterol and elevated triglycerides. Despite these opposing lipid phenotypes, both classes of variant are described as converging on lysosomal cholesterol sequestration and endoplasmic reticulum (ER) cholesterol depletion, with downstream effects on mTOR signalling. The authors propose that variant-specific differences in how STARD9 alters lysosomal positioning produce these opposing trafficking outcomes.

The finding is of potential interest to researchers working on residual cardiovascular risk — defined by the authors as cardiovascular events that persist despite lipid-lowering therapy, independent of LDL cholesterol and Lp(a) — as well as to those studying lysosomal biology and intracellular lipid trafficking. The work has not yet been peer-reviewed, and independent replication of the familial segregation data would be needed to establish STARD9 as a clinically recognised dyslipidaemia gene.