ABCMdb

PMID: 15158913

Albrecht C, Baynes K, Sardini A, Schepelmann S, Eden ER, Davies SW, Higgins CF, Feher MD, Owen JS, Soutar AK
Two novel missense mutations in ABCA1 result in altered trafficking and cause severe autosomal recessive HDL deficiency.
Biochim Biophys Acta. 2004 May 24;1689(1):47-57., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp ApoAI-mediated efflux of cholesterol from the proband`s fibroblasts was less than 10% of normal and nucleotide sequencing revealed inheritance of two novel mutations in ABCAI, V1704D and L1379F. Login to comment 6 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp Severe HDL deficiency in the proband was caused by two novel autosomal recessive mutations in ABCA1, one (V1704D) predicted to lie in a transmembrane segment and the other (L1379F) in a large extracellular loop. Login to comment 23 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp In this study, we describe a patient who has inherited two defective alleles of ABCA1 from apparently unaffected parents, each encoding a previously undescribed single amino acid substitution (L1379F and V1704D). Login to comment 115 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp In the proband, the paternal allele (clear box) carried the L1379F variant of ABCA1, and the maternal allele (shaded box) carried the V1704D variant. Login to comment 116 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp In the proband, the paternal allele (clear box) carried the L1379F variant of ABCA1, and the maternal allele (shaded box) carried the V1704D variant. Login to comment 149 ABCA1 p.Arg219Lys In comparison, the allele frequency of the R219K polymorphism was 0.22 (K allele), similar to that found in other European populations [31]. Login to comment 150 ABCA1 p.Arg219Lys ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp In comparison, the allele frequency of the R219K polymorphism was 0.22 (K allele), similar to that found in other European populations [31]. Login to comment 151 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp The proband`s father was heterozygous for L1379F, and her mother and sister for the V1704D variant (Fig. 1). Login to comment 152 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp Expression of normal and mutant ABCA1 in vitro The L1379F and V1704D mutations were introduced into the full-length cDNA for ABCA1, fused at its carboxyterminus to eGFP. Login to comment 153 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp Expression of normal and mutant ABCA1 in vitro The L1379F and V1704D mutations were introduced into the full-length cDNA for ABCA1, fused at its carboxy-terminus to eGFP. Login to comment 156 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp (a) Confocal sections of transiently transfected HEK 293 cells expressing wild-type ABCA1-eGFP (left panel), ABCA1-eGFP L1379F (middle panel) and ABCA1-eGFP V1704D (right panel); eGFP fluorescence is shown in green and DAPI staining of nuclear DNA in blue. Login to comment 157 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp (a) Confocal sections of transiently transfected HEK 293 cells expressing wild-type ABCA1-eGFP (left panel), ABCA1-eGFP L1379F (middle panel) and ABCA1-eGFP V1704D (right panel); eGFP fluorescence is shown in green and DAPI staining of nuclear DNA in blue. Login to comment 158 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp (b) HEK 293 cells expressing wild-type ABCA1-eGFP, ABCA1-eGFP L1379F and ABCA1-eGFP V1704D were stained for SERCA 2 as an ER marker. Login to comment 159 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp (b) HEK 293 cells expressing wild-type ABCA1-eGFP, ABCA1-eGFP L1379F and ABCA1-eGFP V1704D were stained for SERCA 2 as an ER marker. Login to comment 160 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp A large extent of co-localisation was found for both mutants, suggesting retention of L1379F and V1704D in the ER. Login to comment 161 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp A large extent of co-localisation was found for both mutants, suggesting retention of L1379F and V1704D in the ER. Login to comment 174 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp Discussion We describe a patient of English origin with severe HDL deficiency and premature coronary disease who is heterozygous for two rare alleles of ABCA1 that are predicted to cause single amino acid substitutions, L1379F and V1704D. Login to comment 175 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp Discussion We describe a patient of English origin with severe HDL deficiency and premature coronary disease who is heterozygous for two rare alleles of ABCA1 that are predicted to cause single amino acid substitutions, L1379F and V1704D. Login to comment 205 ABCA1 p.Leu1379Phe The position of the L1379F substitution in ABCA1 is indicated in bold; the residues predicted by Simple Modular Architecture Research Tool (SMART; http://www.smart.embl-heidelberg.de) analysis of the amino acid sequence of ABCA1 to form membrane-spanning segment 7 in ABCA1 and ABCA4 are underlined. Login to comment 206 ABCA1 p.Leu1379Phe ABCA1 p.Val1704Asp The position of the L1379F substitution in ABCA1 is indicated in bold; the residues predicted by Simple Modular Architecture Research Tool (SMART; http://www.smart.embl-heidelberg.de) analysis of the amino acid sequence of ABCA1 to form membrane-spanning segment 7 in ABCA1 and ABCA4 are underlined. Login to comment 207 ABCA1 p.Val1704Asp (b) Above, alignment of human, mouse and chicken ABCA1 and below, human ABCA1 with human ABCA4, showing the position of the V1704D mutation in ABCA1 (indicated in bold). Login to comment 212 ABCA1 p.Leu1379Phe The other amino acid substitution, L1379F, is predicted to lie in the extracellular loop between transmembrane segments 7 and 8 that may constitute the binding site for apoAI [41]. Login to comment 213 ABCA1 p.Leu1379Phe The other amino acid substitution, L1379F, is predicted to lie in the extracellular loop between transmembrane segments 7 and 8 that may constitute the binding site for apoAI [41]. Login to comment 214 ABCA1 p.Cys1477Arg ABCA1 p.Ser1506Leu Two of these, C1477R and S1506L, do not appear to disrupt transport of the protein to the cell surface, as judged by the accessibility of the protein in non-permeabilised cells, but the mutant proteins are unable to mediate cholesterol efflux [38]. Login to comment 215 ABCA1 p.Cys1477Arg ABCA1 p.Ser1506Leu Two of these, C1477R and S1506L, do not appear to disrupt transport of the protein to the cell surface, as judged by the accessibility of the protein in non-permeabilised cells, but the mutant proteins are unable to mediate cholesterol efflux [38]. Login to comment