title: Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency.
abstract: The objective of the study was the characterization of ABCA1 gene mutations in 10 patients with extremely low HDL-cholesterol. Five patients (aged 6 months to 76 years) presented with splenomegaly and thrombocytopenia suggesting the diagnosis of Tangier disease (TD). Three of them were homozygous for novel mutations either in intron (c.4465-34A>G) or in exons (c.4376delT and c.5449C>T), predicted to encode truncated proteins. One patient was compound heterozygous for a nucleotide insertion (c.1758_1759insG), resulting in a truncated protein and for a nucleotide substitution c.4799A>G, resulting in a missense mutation (p.H1600R). The last TD patient, found to be heterozygous for a known mutation (p.D1009Y), had a complete defect in ABCA1-mediated cholesterol efflux in fibroblasts, suggesting the presence of a second undetected mutant allele. Among the other patients, four were asymptomatic, but one, with multiple risk factors, had severe peripheral artery disease. Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. The pathogenic effect of the two intronic mutations (c. 1195-27G>A and c.4465-34A>G) was demonstrated by the analysis of the transcripts of splicing reporter mutant minigenes expressed in COS-1 cells. Both mutations activated an intronic acceptor splice site which resulted in a partial intron retention in mature mRNA with the production of truncated proteins. This study confirms the allelic heterogeneity of TD and suggests that the diagnosis of TD must be considered in patients with an unexplained splenomegaly, associated with thrombocytopenia and hypocholesterolemia.
authors.affiliation: Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, Modena, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Fasano
authors.forename: Paolo
authors.initials: P
authors.lastname: Zanoni
authors.forename: Claudio
authors.initials: C
authors.lastname: Rabacchi
authors.forename: Livia
authors.initials: L
authors.lastname: Pisciotta
authors.forename: Elda
authors.initials: E
authors.lastname: Favari
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Adorni
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Deegan
authors.forename: Adrian
authors.initials: A
authors.lastname: Park
authors.forename: Thinn
authors.initials: T
authors.lastname: Hlaing
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feher
authors.forename: Ben
authors.initials: B
authors.lastname: Jones
authors.forename: Asli Subasioglu
authors.initials: AS
authors.lastname: Uzak
authors.forename: Fatih
authors.initials: F
authors.lastname: Kardas
authors.forename: Andrea
authors.initials: A
authors.lastname: Dardis
authors.forename: Annalisa
authors.initials: A
authors.lastname: Sechi
authors.forename: Bruno
authors.initials: B
authors.lastname: Bembi
authors.forename: Pietro
authors.initials: P
authors.lastname: Minuz
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
authors.forename: Franco
authors.initials: F
authors.lastname: Bernini
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D008076:Cholesterol, HDL / Q000172:deficiency*; D005091:Exons; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007223:Infant; D007438:Introns; D008297:Male; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D013631:Tangier Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D022821:RNA Splice Sites; D012333:RNA, Messenger