Alan T. Remaley1, Stephan Rust1, Marie Rosier1, Cathy Knapper1, Laurent Naudin1, Cyril Broccardo1, Katherine Peterson1, Christine Koch1, Isabelle Arnould1, Catherine Prades1, Nicholas Duverger1, Harald Funke1, Gerd Assman1, Maria Dinger1, Michael Dean1, Giovanna Chimini1, Silvia Santamarina-Fojo1, Donald S. Fredrickson1, Patrice Denèfle1, H. Bryan Brewer1
1National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, MD 20892; Core Genomics and Cardiovascular Department, Rhone-Poulenc Rorer, 91006 Every, France; Institut fur Arterioskleroseforschung an der Westfalischen Wilhelms-Universitat Munster, Domagkstrabe, D-48149 Munster, Germany; Centre d’Immunologie de Marseille-Luminy, 13288 Marseille, France; and National Institutes of Health, National Cancer Institute, Frederick, MD 21702
Tóm tắt
Tangier disease is characterized by low serum high density lipoproteins and a biochemical defect in the cellular efflux of lipids to high density lipoproteins.
ABC1
, a member of the ATP-binding cassette family, recently has been identified as the defective gene in Tangier disease. We report here the organization of the human
ABC1
gene and the identification of a mutation in the
ABC1
gene from the original Tangier disease kindred. The organization of the human
ABC1
gene is similar to that of the mouse
ABC1
gene and other related
ABC
genes. The
ABC1
gene contains 49 exons that range in size from 33 to 249 bp and is over 70 kb in length. Sequence analysis of the
ABC1
gene revealed that the proband for Tangier disease was homozygous for a deletion of nucleotides 3283 and 3284 (TC) in exon 22. The deletion results in a frameshift mutation and a premature stop codon starting at nucleotide 3375. The product is predicted to encode a nonfunctional protein of 1,084 aa, which is approximately half the size of the full-length ABC1 protein. The loss of a
Mnl
1 restriction site, which results from the deletion, was used to establish the genotype of the rest of the kindred. In summary, we report on the genomic organization of the human
ABC1
gene and identify a frameshift mutation in the
ABC1
gene of the index case of Tangier disease. These results will be useful in the future characterization of the structure and function of the
ABC1
gene and the analysis of additional
ABC1
mutations in patients with Tangier disease.
