Novel Missense LCAT Gene Mutation Associated with an Atypical Phenotype of Familial LCAT Deficiency in Two Portuguese Brothers

Abstract

Familial lecithin-cholesterol acyltransferase deficiency (FLD) is a rare recessive disorder of cholesterol metabolism, caused by loss-of-function mutations in the human LCAT gene, leading to alterations in the lipid/lipoprotein profile, with extremely low HDL levels.The classical FLD phenotype is characterized by diffuse corneal opacification, haemolytic anaemia and proteinuric chronic kidney disease (CKD); an incomplete form, only affecting the corneas, has been reported in a few families worldwide.We describe an intermediate phenotype of LCAT deficiency, with CKD preceding the development of corneal clouding, in two Portuguese brothers apparently homozygous for a novel missense LCAT gene mutation. The atypical phenotype, the diagnosis of membranous nephropathy in the proband's native kidney biopsy, the late-onset and delayed recognition of the corneal opacification, the co-segregation with Gilbert syndrome and the late recurrence of the primary disease in kidney allograft all contributed to obscure the diagnosis of an LCAT deficiency syndrome for many years.A major teaching point is that on standard light microscopy examination the kidney biopsies of patients with LCAT deficiency with residual enzyme activity may not show significant vacuolization and may be misdiagnosed as membranous nephropathy. The cases of these two patients also illustrate the importance of performing detailed physical examination in young adults presenting with proteinuric CKD, as the most important clue to the diagnosis of FLD is in the eyes.

Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol

“…Arg244 is a position commonly mutated in LCAT genetic disease (R244G ( McLean, 1992 ; Vrabec et al, 1988 ), R244H ( Pisciotta et al, 2005 ; Sampaio et al, 2017 ; Strøm et al, 2011 ), R244C ( Charlton-Menys et al, 2007 ), and R244L ( Castro-Ferreira et al, 2018 )) and its side chain forms unique interactions in the observed active and inactive states of LCAT. In data obtained from patient plasma, the amount of LCAT-R244G isolated from homozygotes was ~25% of the amount from WT LCAT plasma and there was ~15% of WT LCAT activity, whereas heterozygotes of the R244G and R244H mutations had ~80% and~50% of WT LCAT activity, respectively ( Pisciotta et al, 2005 ; Vrabec et al, 1988 ), thus supporting an important role for this residue.…”

“…The ability to perform rational design is important because we also demonstrated here the therapeutic potential of using small molecule activators targeting the MBD in FLD patients. We focused on mutations at Arg244 ( Castro-Ferreira et al, 2018 ; Charlton-Menys et al, 2007 ; McLean, 1992 ; Pisciotta et al, 2005 ; Sampaio et al, 2017 ; Strøm et al, 2011 ; Vrabec et al, 1988 ) because of its apparent role in the switch mechanism of the active site lid, but in principle any patient harboring an alternative missense mutation that does not directly perturb the hydrolase active site may also benefit from this compound series. In this sense the ability of piperidinylpyrazolopyridine LCAT activators to rescue Arg244 mutants parallels the allosteric action of ivacaftor on the G551D mutant of the cystic fibrosis transmembrane conductance regulator, although their mechanisms of action are necessarily different due to the unique structure of the MBD ( McPhail and Clancy, 2013 ).…”

Gene Mutation Classification through Text Evidence Facilitating Cancer Tumour Detection

“…These gene mutations have variations in sizes, and they can influence every DNA component to a very vast portion of a chromosome that inculcates multiple genes [ 8 ]. Some of the genetic disorders caused due to this include cystic fibrosis, colour blindness, and phenylketonuria among multiple others [ 9 ]. Cancer has resulted from a sequence of mutations occurring within a single cell.…”

Two novel variants in the lecithin:cholesterol acyltransferase gene resulted in classic LCAT deficiency

“…Their clinical courses differed as the second brother still has preserved global renal function despite the same variants and undetectable LCAT enzyme activity and CER in both patients. However, such distinctions were already described in the literature [ 15 ]. An additional contribution to the more rapid course of kidney failure in the first case may be the use of immunosuppressants with potential nephrotoxic effect.…”