Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.
Level 4 - case-series / case-control
In vitro mechanistic characterization combined with a single human case report
PubMed 16909389 · doi:10.1086/507488
What was done
Investigated the cellular mechanisms of four PCSK9 loss-of-function mutations by assessing protein synthesis, trafficking, and secretion kinetics in vitro relative to wild-type PCSK9. Analyzed human plasma via immunoprecipitation and immunoblotting to measure circulating PCSK9 and lipid profiles in individuals with inactivating mutations.
What was found
Recombinant wild-type PCSK9 was secreted from cells into culture medium within 2 hours, whereas the four loss-of-function mutations largely abolished PCSK9 secretion. A compound heterozygote for two inactivating mutations had no immunodetectable circulating PCSK9, had an LDL-C level of 14 mg/dL, and was reported as healthy and fertile.
Why it matters
Provides direct human genetic and mechanistic proof that complete absence of circulating PCSK9 causes extremely low LDL-C without overt adverse effects, establishing PCSK9 as a viable target for cholesterol-lowering therapeutics.
Limits
Clinical and safety observations rely on a single human case (n = 1). The abstract does not report broader cardiovascular outcomes or quantitative safety parameters beyond apparent good health and fertility.
Cited by
- supports Dr. Helen Hobbs discovered in the early to mid-2000s that individuals with loss-of-function/hypofunctioning mutations in the PCSK9 gene have LDL cholesterol levels around 10 to 20 mg/dL and are protected against cardiovascular disease.