[After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9].
The genes encoding the low-density lipoproteins receptor and its ligand apolipoprotein B, have been the only two genes classically implicated in autosomal dominant hypercholesterolemia. We have identified in 2003, the third gene implicated in this disease: PCSK9 (Proprotein Convertase Subtilin Kexin 9). Several mutations (p.S127R, p.F216L, p.D374Y...) of this gene have been reported to cause hypercholesterolemia by a gain of function leading to a reduction of LDL receptor levels. Other variations of PCSK9 are conversely associated with hypocholesterolemia particularly the non-sense p.Y142X and p.C679X mutations found in 2% of black Americans and associated with a decrease of LDL levels and coronary heart diseases. PCSK9 substrates and exact role have not been elucidated yet, but it seems that PCSK9 is definitely a major actor in cholesterol homeostasis. PCSK9 inhibitors might constitute new therapeutic targets that would decrease plasma LDL cholesterol levels and be synergistic with statin drugs.
Abifadel
M
M
Inserm, U781, Paris, France. abifadel@necker.fr
Rabès
J-P
JP
Boileau
C
C
Varret
M
M
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D013381:Subtilisins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics
D001055:Apolipoproteins B; D011973:Receptors, LDL; D014157:Transcription Factors; C099101:PCSK7 protein, human; D013381:Subtilisins