LCAT deficiency: molecular and phenotypic characterization of an Italian family.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is an autosomal recessive disorder of lipoprotein metabolism, resulting from loss of function of lecithin:cholesterol acyltransferase (LCAT; EC 2.3.1.43), a key enzyme in extracellular cholesterol metabolism and reverse cholesterol transport (RCT). The human LCAT gene has been mapped to chromosome band 16q22, and consists of 6 exons encoding for a mature protein of 416 amino acids. In the present study, we describe the molecular phenotype of a patient with classical LCAT deficiency and progressive renal failure. Sequence analysis of the LCAT gene showed 2 homozygous missense mutations: the common variant p.S208T, described as a homozygous change for the first time, and a missense mutation characterized by the substitution of Leu372 to Arg. Clinical, biochemical and renal histological studies were also performed to elucidate the functional effects of these variations. In the proband and his brother, LCAT activity and plasma cholesterol esterification rate (CER) were absent, while plasma LCAT concentrations were slightly reduced. By light microscopy, silver-stained renal biopsy specimens of the proband showed focal segmental glomerulosclerosis, while electron microscopy detected lipid deposits with both vacuolar lucent appearance and electron-dense lamellar structures within the mesangial matrix and glomerular basement membrane. This study describes for the first time the occurrence of two homozygous missense mutations as the common variant p.S208T and the mutation p.L372R in familial LCAT deficiency.