IDENTIFICATION OF THE NOVEL PCSK9-Q152H LOSS-OF-FUNCTION
VARIANT IN A FRENCH-CANADIAN FAMILY
To this end the researchers performed a reverse genetic loss-of-function
screen with a small interfering RNA (siRNA) library representing 160 kinases.
The MC4R pathway is well validated in humans; loss-of-function
mutations of MC4R are associated with obesity and have a reported prevalence of 4%-6% in severe obesity.
We wanted to uncover general principles that could be applied to a variety of loss-of-function
protein misfolding diseases.
alleles (G946A, A1513C, and T1729A) have been characterized in recombinant expression systems, and similar methods have recently been used to characterize a gain-of-function allele (C489T) (20-23).
2003) presented the results of an investigation of more than 16,000 genes for loss-of-function
phenotypes in C.
A point mutation at R345T which appears to result in loss-of-function
when re-expressed in the mouse was found in 5925 healthy individuals with a heterozygous frequency of approximately 0.
The discovery of loss-of-function
mutations for this target in humans with protective cardiovascular profiles was central for the development of compound modulators of the target.