Novel missense variants in LCAT and APOB genes in an Italian kindred with familial lecithin:cholesterol acyltransferase deficiency and hypobetalipoproteinemia.
BACKGROUND
Lecithin:cholesterol acyltransferase (LCAT) is responsible for cholesterol esterification in plasma. Mutations of LCAT gene cause familial LCAT deficiency, a metabolic disorder characterized by hypoalphalipoproteinemia. Apolipoprotein B (apoB) is the main protein component of very-low-density lipoproteins and low-density lipoprotein (LDL). Mutations of APOB gene cause familial hypobetalipoproteinemia, a codominant disorder characterized by low plasma levels of LDL cholesterol and apoB.


OBJECTIVE
This was a genetic and biochemical analysis of an Italian kindred with hypobetalipoproteinemia whose proband presented with hypoalphalipoproteinemia and severe chronic kidney disease.


METHODS
Plasma lipids and apolipoproteins, cholesterol esterification, and high-density lipoprotein (HDL) subclass distribution were analyzed. LCAT and APOB genes were sequenced.


RESULTS
The proband had severe impairment of plasma cholesterol esterification and high preβ-HDL content. He was heterozygote for the novel LCAT P406L variant, as were two other family members. The proband's wife and children presented with familial hypobetalipoproteinemia and were heterozygotes for the novel apoB H1401R variant. Cholesterol esterification rate of apoB H1401R carriers was reduced, likely attributable to the low amount of circulating LDL. After renal transplantation, proband's lipid profile, HDL subclass distribution, and plasma cholesterol esterification were almost at normal levels, suggesting a mild contribution of the LCAT P406L variant to his pretransplantation severe hypoalphalipoproteinemia and impairment of plasma cholesterol esterification.


CONCLUSIONS
LCAT P406L variant had a mild effect on lipid profile, HDL subclass distribution, and plasma cholesterol esterification. ApoB H1401R variant was identified as possible cause of familial hypobetalipoproteinemia and resulted in a reduction of cholesterol esterification rate.
Center E. Grossi Paoletti, Department of Pharmacological Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
Paola
P
Conca
Silvana
S
Pileggi
Sara
S
Simonelli
Emanuela
E
Boer
Giuliano
G
Boscutti
Lucia
L
Magnolo
Patrizia
P
Tarugi
Silvana
S
Penco
Guido
G
Franceschini
Laura
L
Calabresi
Monica
M
Gomaraschi
D016632:Apolipoprotein A-I / Q000097:blood; D001055:Apolipoproteins B / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood; D004951:Esterification; D006579:Heterozygote; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000235:genetics* / Q000628:therapy; D007558:Italy; D016030:Kidney Transplantation; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D014280:Triglycerides; D007862:Phosphatidylcholine-Sterol O-Acyltransferase