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Hypobetalipoproteinemia and Developmental Abnormalities in Mice (Embryonic Stem Cells/Gene Targeting/Hydrocephalus/Exencephalus/Atherosclerosis) GREGG E

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Hypobetalipoproteinemia and Developmental Abnormalities in Mice (Embryonic Stem Cells/Gene Targeting/Hydrocephalus/Exencephalus/Atherosclerosis) GREGG E Proc. Natl. Acad. Sci. USA Vol. 90, pp. 2389-2393, March 1993 Medical Sciences Targeted modification of the apolipoprotein B gene results in hypobetalipoproteinemia and developmental abnormalities in mice (embryonic stem cells/gene targeting/hydrocephalus/exencephalus/atherosclerosis) GREGG E. HoMANICS*, TERRY J. SMITH*t, SUNNY H. ZHANG*, DENISE LEE*, STEPHEN G. YOUNGf, AND NOBUYO MAEDA*§ *Department of Pathology, The University of North Carolina at Chapel Hill, CB #7525, Chapel Hill, NC 27599-7525; and tGladstone Foundation Laboratories for Cardiovascular Disease, Cardiovascular Research Institute, Department of Medicine, The University of California, San Francisco, CA 94110-0608 Communicated by Oliver Smithies, December 17, 1992 (receivedfor review November 10, 1992) ABSTRACT Familial hypobetalipoproteinemia is an auto- proteins (for reviews, see refs. 7 and 8). Such mutations cause somal codominant disorder resulting in a dramatic reduction in familial hypobetalipoproteinemia (HBL), a condition char- plasma concentrations of apolipoprotein (apo) B, cholesterol, acterized by a reduction in circulating apoB, cholesterol, and and ,-migrating lipoproteins. A benefit of hypobetalipopro- ,-lipoproteins. Humans homozygous for "null alleles" have teinemia is that mildly affected individuals may be protected a complete absence of apoB-containing lipoproteins and can from coronary vascular disease. We have used gene targeting be severely affected with symptoms of intestinal fat malab- to generate mice with a modified Apob allele. Mice containing sorption, fat-soluble vitamin deficiency, and neurological this allele display all of the hallmarks of human hypobetali- problems. The phenotypes of individuals homozygous for poproteinemia: they produce a truncated apoB protein, mutant APOB alleles leading to the synthesis of truncated apoB70, and have markedly decreased plasma concentrations apoB proteins are variable (7-10). Heterozygotes have one- of apoB, ,B-lipoproteins, and total cholesterol. In addition, the third to one-half of normal apoB and LDL-cholesterol levels mice manifest several characteristics that are occasionally and are almost always asymptomatic. Because of their low observed in human hypobetalipoproteinemia, including re- cholesterol levels, heterozygotes appear to be protected from duced plasma triglyceride concentrations, fasting chylomicro- coronary vascular disease and have a longer life expectancy nemia, and reduced high density lipoprotein cholesterol. An (10). unexpected finding is that the modified Apob allele is strongly Progress is being made toward understanding atherogen- associated with exencephalus and hydrocephalus. These mice esis by investigating humans and animals that are genetically should help increase our understanding of hypobetalipopro- prone to hyperlipidemia. A valid alternative is to study teinemia, atherogenesis, and the eitiology of exencephalus and humans and animals that are genetically protected from hydrocephalus. cardiovascular disease. With this in mind, we have generated a mouse model of HBL. To do this, we used a sequence insertion vector to disrupt exon 26 ofthe Apob gene in mouse Apolipoprotein (apo) B is a major structural component of embryonic stem (ES) cells. Mice carrying this disrupted gene very low density lipoprotein (VLDL), intermediate density synthesize apoB48 and a truncated apoB (apoB70) but no lipoprotein (IDL), low density lipoprotein (LDL), chylomi- apoBlOO. The lipoprotein phenotype of the mice is remark- crons, and lipoprotein(a). High plasma levels of apoB- ably similar to familial HBL in humans. Quite unexpectedly, containing lipoproteins are associated with an increased risk however, some of the mice also exhibit exencephalus and of coronary artery disease (1). apoB normally exists in two hydrocephalus, pathologic features that have never, to our forms, apoB100 and apoB48; both are the product ofthe same knowledge, been reported in human HBL. gene (2). The human gene spans 43 kb of DNA and contains 29 exons (3). MATERIALS AND METHODS apoBlOO, which contains 4536 amino acids, is synthesized Preparation of Targeting Constructs. An =l11-kb Bgl II exclusively in the liver and is secreted into the circulation as fragment containing exon 26 of the Apob gene was isolated a surface component of triglyceride-rich VLDL. It is a ligand from STO cell DNA (11). Two oligonucleotides which encode for the LDL receptor and is responsible for receptor- peptides of human f3s-globin (amino acids 1-12 and 120-131) mediated clearance of LDL by the liver and other organs. were used to replace nucleotides located in exon 26 of the Amino acids 3146-3159 and amino acids 3357-3368 are Apob gene (see Fig. 1) that encode two short amino acid thought to be important components of the LDL receptor- sequences thought to be important in binding to the LDL binding domain of apoBlOO (4). receptor (4). An in-frame stop codon was inadvertently apoB48 is formed as a result of post-transcriptional editing inserted into the 5' 3s-globin sequence while making the ofapoB mRNA, which changes codon 2153 into a stop codon constructs, but its presence later proved beneficial to the (5, 6). apoB48 is synthesized in small intestine and is required outcome of the experiments. 0-type (insertion) targeting for the packaging of dietary lipids into chylomicrons. A large plasmids were constructed with an 8.3-kb HindIII fragment percentage of mouse hepatic apoB mRNA is edited, indicat- ofthe Apob gene which includes the ,35-globin modifications, ing that the mouse probably makes apoB48 in the liver (D. F. an HPRT minigene [pnI2(IlS) of Reid et al. (12)], and Johnson, personal communication). apoB48 lacks the puta- pBluescript (Stratagene) (Fig. 1B). Constructs were made tive LDL receptor-binding domain of apoBlOO and does not interact with the LDL receptor. Abbreviations: HBL, hypobetalipoproteinemia; apo, apolipoprotein; In humans, many mutations in the APOB gene have been HDL, high density lipoprotein; LDL, low density lipoprotein; VLDL, identified that prevent the translation of full-length apoB very low density lipoprotein; IDL, intermediate density lipoprotein; ES cells, embryonic stem cells; HPRT, hypoxanthine phosphoribo- syltransferase. The publication costs of this article were defrayed in part by page charge tPresent address: BioResearch Ireland, National Diagnostic Centre, payment. This article must therefore be hereby marked "advertisement" University College, Galway, Ireland. in accordance with 18 U.S.C. §1734 solely to indicate this fact. §To whom reprint requests should be addressed. 2389 Downloaded by guest on September 30, 2021 2390 Medical Sciences: Homanics et al. Proc. Natl. Acad. Sci. USA 90 (1993) A - 11.0 kb _ retro-orbital bleeding into tubes containing 0.3 mg of EDTA, 25 mg of gentamycin sulfate, and 11.5 milliunits of aprotinin (Sigma). Plasma was collected by centrifugation at 14,000 x probe B probe A g for 10 min at 4°C. Agarose gel electrophoresis of whole plasma and determination of total cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride were as pre- B **+ viously described (17, 18). Lipoproteins were fractionated by sequential density ul- tracentrifugation (18). Fractions were concentrated and de- salted by using a Centricon-10 (Amicon) apparatus according probe C to the manufacturer's protocol, and 20 ,ug of protein from each fraction was electrophoresed on an SDS/3-20% poly- C 16I16.5 kb 17.5 kb 12/12.5 kb acrylamide gradient gel (16 x 16 x 1.5 mm) at 150 V for 6 hr (18). The size of lipoproteins in the d (density) < 1.006 g/ml fraction of mouse plasma was assessed by electron micros- copy (19). Whole plasma apoAI concentrations were quan- term. P1 P2 tified by nonreducing gel electrophoresis as described by France et al. (20). FIG. 1. (A) Endogenous Apob locus, showing relative location of Northern Blot Analysis. Total RNA was prepared, electro- sequences coding for LDL receptor-binding domains (white boxes) phoresed, transferred to Hybond-N (Amersham), and hy- within exon 26 (solid black box). The horizontal arrow illustrates the bridized as described (21). Probes used include probes A, B, size of the endogenous Bgl II fragment. Probe A is a 1.1-kb C (see Fig. 1), apoAl (22), and human j3actin (Clontech). HindIII/Bgl II fragment. Probe B is a 2.35-kb EcoRI fragment. (B) Insertion type targeting construct. The sequences that encode the RESULTS AND DISCUSSION LDL receptor-binding domains of the endogenous Apob locus have Targeting of the been replaced with 1s-globin sequences as indicated by asterisks. Apob Locus in Mouse ES Cells. The scheme The downward arrow indicates the Sac I site used to linearize the of targeting of the Apob locus is illustrated in Fig. 1. A total construct prior to electroporation. Probe C hybridizes to plasmid of 1967 HPRT+ ES cell colonies were screened by PCR for vector sequences (thin line). H in stippled box indicates hypoxan- homologous recombination at the Apob locus. From 23 thine phosphoribosyltransferase (HPRT) DNA. (C) Targeted Apob PCR-positive colonies, 6 lines of ES cells were established in locus of cell line ESapoB6-3, which contains three repeats of Apob which targeting at the Apob locus was confirmed by Southern sequences that include the ps-globin modifications. In this locus, the blot analysis (Fig. 2). Probe A, which is external to the HPRT gene is in the opposite transcriptional orientation from the targeting DNA, detected an 11-kb Bgl II fragment from the Apob gene. The expected sizes of the Bgl II fragments
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