TY - JOUR
T1 - Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia
AU - Lehrman, Mark A.
AU - Goldstein, Joseph L.
AU - Russell, David W.
AU - Brown, Michael S.
N1 - Funding Information:
We thank Edith Womack and Lavon Sanders for able assistance in growing the cultured cells. Mark Woelfle and Daniel Putnam provided excellent technical assistance. This research was supported by research grants from the National Institutes of Health (HL 20948) and the Robert A. Welch Foundation (I-971). M. A. L. is the recipient of a fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. D. W. Ft. is the recipient of a Research Career Development Award from the National Institutes of Health (HL 01287). M. A. L:s present address is: Department of Pharmacology, University of Texas Health Science Center at Dallas, Dallas, Texas 75235 The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
PY - 1987/3/13
Y1 - 1987/3/13
N2 - A defective LDL receptor gene in a child with familial hypercholesterolemia produces a receptor precursor that is 50,000 daltons larger than normal (apparent Mr 170,000 vs. 120,000). The elongated protein resulted from a 14 kilobase duplication that encompasses exons 2 through 8. The duplication arose from an unequal crossing-over between homologous repetitive elements (Alu sequences) in intron 1 and intron 8. The mutant receptor has 18 contiguous cysteine-rich repeat sequences instead of the normal nine. Seven of these duplicated repeats are derived from the ligand-binding domain, and two repeats are part of the epidermal growth factor precursor homology region. The elongated receptor undergoes normal carbohydrate processing, its apparent molecular weight increases to 210,000, and the receptor reaches the cell surface where it binds reduced amounts of LDL but undergoes efficient internalization and recycling. The current findings support an evolutionary model in which homologous recombination between repetitive elements in introns leads to exon duplication during evolution of proteins.
AB - A defective LDL receptor gene in a child with familial hypercholesterolemia produces a receptor precursor that is 50,000 daltons larger than normal (apparent Mr 170,000 vs. 120,000). The elongated protein resulted from a 14 kilobase duplication that encompasses exons 2 through 8. The duplication arose from an unequal crossing-over between homologous repetitive elements (Alu sequences) in intron 1 and intron 8. The mutant receptor has 18 contiguous cysteine-rich repeat sequences instead of the normal nine. Seven of these duplicated repeats are derived from the ligand-binding domain, and two repeats are part of the epidermal growth factor precursor homology region. The elongated receptor undergoes normal carbohydrate processing, its apparent molecular weight increases to 210,000, and the receptor reaches the cell surface where it binds reduced amounts of LDL but undergoes efficient internalization and recycling. The current findings support an evolutionary model in which homologous recombination between repetitive elements in introns leads to exon duplication during evolution of proteins.
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U2 - 10.1016/0092-8674(87)90079-1
DO - 10.1016/0092-8674(87)90079-1
M3 - Article
C2 - 3815525
AN - SCOPUS:0023610526
SN - 0092-8674
VL - 48
SP - 827
EP - 835
JO - Cell
JF - Cell
IS - 5
ER -