Istituto di Fisiologia Clinica     
Bocchi L., Pisciotta L., Fasano T., Candini C., Puntoni M., Sampietro T., Bertolini S., Calandra S. Multiple abnormally spliced ABCA1 mRNAs caused by a novel splice site mutation of ABCA1 gene in a patient with Tangier disease. In: Clinica Chimica Acta, vol. 411 pp. 524 - 530. Clinica Chimica Acta, 2010.
Background: Mutations in ABCA1 gene are the cause of Tangier disease (TD) and familial high density lipoprotein (HDL) deficiency. Splice site mutations of this gene were reported infrequently. Methods: ABCA1 gene was sequenced in a TD patient and in subjects with lowHDL. The effect of intronic variants on ABCA1 pre-mRNA splicing was studied in COS-1 cells expressing a mutant minigene or in patients' cells. Results: A novel mutation in intron 20 (c.2961 -2 A>C) was found in the TD patient. To assess its effect, a mutant ABCA1 minigene, containing intron 18-intron 23 region, was expressed in COS-1 cells. The mutant minigene generated three transcripts: i) in the first (459 bp) 61 nucleotides of intron 20 were retained; ii) in the second (384 bp) exon 20 joined to exon 21 devoid of the first 14 nucleotides; and iii) in the third (255 bp) the entire exon 21 was skipped. The first two transcripts were also observed in patient's peripheral blood mononuclear cells. These mRNAs encode truncated proteins. A variant in intron 8 (c.814 −14 ins A), identified in subjects with low HDL, had no effect on ABCA1 pre-mRNA splicing. Conclusions: Functional analysis is required to establish the effect of intronic mutations on ABCA1 pre-mRNA splicing.
Subject Tangier disease
ABCA1 gene
Intronic mutations
Splicing defects
Truncated proteins

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