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Originally published In Press as doi:10.1194/jlr.M200438-JLR200 on March 1, 2003

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Journal of Lipid Research, Vol. 44, 911-916, May 2003
Copyright © 2003 by Lipid Research, Inc.

A missense mutation in the Abcg5 gene causes phytosterolemia in SHR, stroke-prone SHR, and WKY rats

Kylie A. Scoggan1, Heidi Gruber and Katherine Larivière

Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Banting Research Centre, Ottawa, Ontario, Canada

Published, JLR Papers in Press, March 1, 2003. DOI 10.1194/jlr.M200438-JLR200

1 To whom correspondence should be addressed. e-mail: kylie_scoggan{at}hc-sc.gc.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sitosterolemia is an autosomal recessive disorder caused by mutations in the ABCG5 or ABCG8 half-transporter genes. These mutations disrupt the mechanism that distinguishes between absorbed sterols and is most prominently characterized by hyperabsorption and impaired biliary elimination of dietary plant sterols. Sitosterolemia patients retain 15–20% of dietary plant sterols, whereas normal individuals absorb less than 1–5%. Normotensive Wistar Kyoto inbred (WKY inbred), spontaneously hypertensive rat (SHR), and stroke-prone spontaneously hypertensive rat (SHRSP) strains also display increased absorption and decreased elimination of dietary plant sterols. To determine if the genes responsible for sitosterolemia in humans are also responsible for phytosterolemia in rats, we sequenced the Abcg5 and Abcg8 genes in WKY inbred, SHR, and SHRSP rat strains. All three strains possessed a homozygous guanine-to-thymine transversion in exon 12 of the Abcg5 gene that results in the substitution of a conserved glycine residue for a cysteine amino acid in the extracellular loop between the fifth and sixth membrane-spanning domains of the ATP binding cassette half-transporter, sterolin-1.

The identification of this naturally occurring mutation confirms that these rat strains are important animal models of sitosterolemia in which to study the mechanisms of sterol trafficking.

Supplementary key words sitosterolemia • sterolin-1 • ATP binding cassette half-transporter • spontaneously hypertensive rats • plant sterols


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sitosterolemia (MIM 210250), also known as phytosterolemia, is a rare autosomal recessive disorder characterized by increased absorption and decreased elimination of dietary plant sterols, as well as abnormally low cholesterol biosynthesis (1–4). Affected individuals have high levels of plasma plant sterols, namely 18–72 mg/dl versus 0.3–1.0 mg/dl (W. M. N. Ratnayake, and E. Vavasour, unpublished observations) and normal to slightly elevated blood cholesterol levels. Patients exhibit tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Recently, mutations in the ATP binding cassette (ABC) half-transporter genes ABCG5 and ABCG8 have been shown to cause sitosterolemia in humans (5, 6). These genes are oriented on chromosome 2p21 in a head-to-head arrangement, are separated by 375 bp, and each contains 13 exons (7). ABCG5 and ABCG8 genes are members of the ABC transporter family and encode for sterolin-1 and sterolin-2, respectively. These proteins are expressed in liver and intestine and consist of an N-terminal ATP binding site and six transmembrane domains at the C terminus. On the basis of their importance in sitosterolemia and recent expression in transgenic mice (8), these proteins are thought to pump plant sterols out of intestinal cells into the gut lumen, and out of liver cells into the bile duct. Functional ABC transporters comprise two ATP binding sites and 12 membrane-spanning domains (9, 10). Consistent with these half-transporters functioning as heterodimers, mutations in either ABCG5 or ABCG8, but not in both genes simultaneously, have been found in sitosterolemia patients (5–7, 11, 12). To date, no mutations have been identified in these genes in other species. Lu et al. have identified a number of polymorphisms in Abcg5 and Abcg8 in several mouse strains (13) and although some of these polymorphisms altered amino acids, none of them correlated with increased plasma plant sterol levels. Similar to phytosterolemic patients, specific rat strains have been shown to retain high levels of plasma plant sterols and to have blood and cell membrane cholesterol deficiencies (14–17). Normotensive Wistar Kyoto inbred (WKY inbred) rats, spontaneously hypertensive rats (SHRs), and stroke-prone spontaneously hypertensive rats (SHRSPs) contained 12% to 15% plant sterols in the sterol fraction of serum compared with 2% to 6% in nine different rat strains fed commercial rat chow (18). Ikeda et al. (18) further demonstrated that WKY inbred and SHRSP rats deposit three to four times higher levels of plant sterols in serum when fed a 0.5% plant sterol diet. The proportion of plant sterols in the sterol fraction was ~25% to 35% (33.7 mg/dl) in WKY inbred and SHRSP rats and 6% to 12% (8.39 mg/dl) in WKA and Wistar control rats (18). In all tissues, the deposition of campesterol was higher than that of sitosterol. These high serum plant sterol values are similar to those obtained from phytosterolemic patients (4) and by Ratnayake et al. in SHRSP rats (15). The increased accumulation of plant sterols in these rats may be due to enhanced intestinal absorption and decreased biliary excretion (18). The SHRSP strain was derived from the SHR strain (19–21) that had been developed previously from the WKY inbred strain (22). Their serum triacylglycerol levels do not differ significantly (23), and it is well established that dietary plant sterols have no effect on triglycerides in both rats (15) and humans (24). When fed a high cholesterol/cholate diet, the plasma cholesterol levels are significantly higher in normotensive WKY inbred than in SHR and SHRSP strains even though these three rat strains have increasing systolic blood pressures in that order (25). The SHR and SHRSP strains are widely used animal models for hypertension and hemorrhagic stroke and may also be suitable models for studying mechanisms of differential absorption of various sterols. To ascertain the mechanism of increased dietary plant sterol retention in these rats, we determined the genomic structures for the rat Abcg5 and Abcg8 genes and their mRNA tissue expression patterns, and subsequently identified the mutation responsible for phytosterolemia in rats.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Database searches and PCR approach to determine exon/intron boundaries
Accession numbers AF312714.2 and AF351785.1, corresponding to rat Abcg5 and Abcg8 cDNA sequences, respectively, were used to search databases for any homologous genomic DNA sequences using the Basic Local Alignment Search Tool (BLAST). Rat clone CH230-359E1 (AC112747.1) and clone CH230-65H6 (AC120701) were identified from the Rat Genome Database. Using these genomic sequences, we were able to determine the intron sequences flanking all of the exons in the ABC half-transporter genes except for Abcg5 exons 2, 8, and 9, and Abcg8 exons 4, 5, 6, and 8. To determine the remaining exon/intron boundary sequences and estimate intron sizes, rat genomic fragments were amplified using primers selected from the cDNA sequences (Table 1). These fragments were subsequently cloned (TOPO TA Cloning Kit, Invitrogen Life Technologies, Canada) and sequenced.


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  		TABLE 1. Oligonucleotide primers used for amplification of Abcg5 and Abcg8 introns

 
Subject samples
Liver tissue samples were obtained from the following rats: SHRSP (SHRSP from Seac Yoshitomi, Fukuoka, Japan, inbred, SPF, maintained in the Animal Resources Division of Health Canada for 2 years); SHR [Tac:N(SHR) (Okamoto-Aoki Strain), outbred, bred in a closed colony, MPF, Taconic Farms, Inc., Germantown, NY]; WKY (WKY/NMol@Tac, inbred, MPF, Taconic Farms, Inc.); WKY [Tac:N(WKY), outbred, MPF, Taconic Farms, Inc.]; Sprague-Dawley [Crl:CD(SD)IGSBR, outbred, Charles River Canada, Saint-Constant, Quebec]; diabetes-prone and control BB (BBdp and BBc, respectively, Animal Resources Division of Health Canada). Genomic DNA was extracted from the tissue samples using GenElute Mammalian Genomic DNA Miniprep Kit (Sigma Chemical Co., St. Louis, MO).

DNA sequencing analysis
Rat genomic DNA was subjected to PCR and direct DNA sequencing in order to screen the Abcg5 and Abcg8 genes for sequence variations. Primers were designed based on our deduced genomic structures of both genes and were used to amplify all 26 exons from the intronic sequences flanking each exon (Table 2). PCR amplification conditions were optimized for each primer pair, and the products were subsequently subjected to exonuclease I and shrimp alkaline phosphatase treatment (Exo-Sap-It, Amersham, Piscataway, NJ; USB Corp., Cleveland, OH) and then manually sequenced using the Thermo Sequenase Radiolabeled Terminator Cycle Sequencing Kit (Amersham; USB Corp.) according to the manufacturer's recommended conditions. Denatured sequencing reactions were immediately loaded and electrophoresed through a 6% acrylamide gel (SequaGel-6, National Diagnostics, Atlanta, GA). Gels were transferred onto filter paper, dried for 2 h at 80°C, and exposed to X-ray film (KODAK BIOMAX MX, Mandel Scientific, Guelph, ON) for 18 h at -80°C. Autoradiographs were examined for sequence changes. All nucleotide, codon, and exon numbering corresponds to GenBank accession numbers AF312714.3 and AF351785.2 (http://www.ncbi.nlm.nih.gov/).


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  		TABLE 2. Oligonucleotide primersa used for amplification of Abcg5 and Abcg8 exons

 
Restriction enzyme analysis
Several control rat strains were screened for the presence of the G1811T transversion by PCR amplification of exon 12 of the Abcg5 gene followed by HaeIII restriction analysis (New England Biolabs, Beverly, MA). The single nucleotide transversion deletes a unique HaeIII restriction site.

Northern blot analysis
Rat multiple-tissue poly(A)+ RNA Northern blots (Ori-gene, Bethesda, MD) were hybridized with radiolabeled rat Abcg5 cDNA, rat Abcg8 cDNA, or ß-actin cDNA according to the manufacturer's recommended conditions. Primers designed to Abcg5 (forward 5'-GCTCTGAAGCCAGACAGGAC-3'; reverse 5'-GTTCAGGACAGGGGTAACCA-3') or Abcg8 (forward 5'-GAGGACTCAAGTGCCCTAGC-3'; reverse 5'-GTAGATAGGGGTGCCAGACG-3') transcripts were used to PCR amplify probes from cDNA prepared using rat liver total RNA. Total RNA was isolated using Trizol reagent (Invitrogen Life Technologies) as per the manufacturer's recommended conditions. Rat Abcg5 or Abcg8 cDNA was radiolabeled by incorporation of [{alpha}-32P]dCTP into the PCR product, and unincorporated nucleotides were removed using G-50 Micro columns (Amersham) as per the manufacturer's instructions. The activity of the probes was determined by scintillation counting, and 1–3 x 106 cpm of denatured probe was added per ml of hybridization solution.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Genomic structure of Abcg5 and Abcg8 rat genes
Genomic information for Abcg5 and Abcg8 genes was obtained by comparing the full-length cDNA transcripts present in GenBank to sequences deposited in the Rat Genome Database using BLAST. Two clones, CH230-359E1 (AC112747.1) and CH230-65H6 (AC120701), were identified that contained partial genomic fragments for both Abcg5 and Abcg8. These sequences enabled us to quickly determine many of the exon/intron boundaries of the ABC half-transporter genes and importantly, the intron sequences flanking many of the exons of these genes. The remaining exon/intron boundaries and intron sizes were determined by sequencing cloned PCR products produced using exon-specific primers and rat genomic DNA (Table 1). Our results (Table 3) have now been confirmed by updated versions of clones CH230-359E1 (AC112747.3) and CH230-65H6 (AC120701.4) from the Rat Genome Database. Similar to the human and mouse genes, the rat Abcg5 and Abcg8 genes are arranged in a head-to-head orientation, and each gene is composed of 13 exons and 12 introns. The Abcg5 gene spans ~33 kb of genomic DNA and the Abcg8 gene spans about 20 kb, with 379 bp separating their respective initiation codons.


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  		TABLE 3. Exon-intron boundaries and organization of rat Abcg5 and Abcg8 genes

 
Mutation detection
SHRSP, SHR, and WKY inbred DNA was examined for a mutation in the Abcg5 and Abcg8 genes. PCR and direct sequencing analysis identified a guanine-to-thymine transversion at nucleotide position 1,811 (codon 583) in exon 12 of both alleles of the Abcg5 gene (Fig. 1A) . This transversion results in the substitution of a highly conserved glycine residue for a cysteine amino acid in the large extracellular loop between transmembrane domains 5 and 6 of sterolin-1 (Fig. 1B and Fig. 2) , whereas Abcg5 exon 12 from the WKY outbred rat, along with three other rat strains (SD, BBc, and BBdp), displayed only wild-type sequence (Fig. 1A). HaeIII restriction enzyme digests of Abcg5 exon 12 were also negative for the presence of the G1811T mutation in four additional rat strains, Wistar, Long-Evans, Wistar-Furth, and full diabetic (data not shown).



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  		Fig. 1. A guanine-to-thymine transversion in the Abcg5 gene is present in rats with phytosterolemia. A: DNA sequence analysis of the coding strand of exon 12 of the rat Abcg5 gene displays a guanine-to-thymine transversion at nucleotide 1,811 in both alleles (arrow) of WKY inbred (lane 5), SHR (lane 6), and SHRSP (lane 7) rat strains that is not present in SD (lane 1), BBc (lane 2), BBdp (lane 3), and WKY outbred (lane 4) rats. DNA sequence from the autoradiograph is given in the forward orientation starting at nucleotide 1,802. B: Nucleotide and amino acid comparison of wild-type and mutant sequences as a result of the guanine-to-thymine transversion at position 1,811. The guanine-to-thymine transversion is boxed, with the subsequent amino acid change in boldface.

 


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  		Fig. 2. Glycine residue at codon 583 is conserved through evolution. ABCG5 half-transporter amino acids 568 to 601 from several different species are shown. The highly conserved glycine residue is boxed and the cysteine mutation of the WKY inbred, SHR, and SHRSP rat is in boldface.

 
A polymorphism was also present in Abcg5 exon 7 on both alleles from SHRSP, SHR, and WKY inbred rats that was not found in WKY outbred, SD, BBc, and BBdp rat strains (Table 4). This cytosine-to-thymine transition does not result in an amino acid substitution.


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  		TABLE 4. Single nucleotide polymorphisms detected in the rat Abcg5 and Abcg8 genes

 
Several novel polymorphisms were also present in the seven rat strains sequenced, and these are listed in Table 4.

Tissue distribution of rat Abcg5 and Abcg8 mRNA
Northern blot analyses demonstrated that the rat Abcg5 gene is predominantly expressed in liver and small intestine, with a major transcript size of 2.6 kb and fainter transcript sizes of 1.1, 1.3, and 2.2 kb (Fig. 3A) . Overexposure of the rat multiple tissue Northern blot resulted in the detection of faint Abcg5 transcripts in brain, kidney, and skin (data not shown). Rat Abcg8 mRNA expression is also predominant in liver and small intestine (Fig. 3B). Both of these tissues displayed an intense 3.9 kb transcript and a faint 2.6 kb transcript.



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  		Fig. 3 The rat Abcg5 and Abcg8 genes are predominantly expressed in liver and small intestine. Results of Northern blot analyses of poly(A)+ RNA from a variety of rat tissues (see Materials and Methods) are shown, demonstrating in A the expression of Abcg5 (upper box) and ß-actin (lower box) transcripts, and in B, the expression of Abcg8 (upper box) and ß-actin (lower box) transcripts.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we report the first identification of a mutation in the rat Abcg5 gene that is responsible for phytosterolemia. This guanine-to-thymine transversion results in the substitution of a highly conserved glycine residue for a cysteine amino acid in the large extracellular loop between transmembrane domains 5 and 6 of the ABC half-transporter protein, sterolin-1. This mutation was present in both alleles of exon 12 of the Abcg5 gene in WKY inbred, SHR, and SHRSP rats. Our results correlate with previous reports demonstrating increased absorption and retention of plant sterols in the serum and tissues of WKY inbred, SHR, and SHRSP rats (14, 15, 18), and are consistent with the identification of other homozygous missense mutations in the human ABCG5 or ABCG8 genes in sitosterolemia patients (5, 6, 11, 12). The homozygous mutation coincides with the recessive nature of the disease and with the development and inbreeding of these specific rat strains. The SHRSP inbred rat strain was developed from the SHR strain that is maintained in a closed colony (19–21). The SHR strain was derived previously from the normotensive WKY inbred rat strain (22). Based on the above information and on the absence of the glycine-to-cysteine amino acid substitution in the eight different rat strains tested, the data strongly suggest that the alteration at codon 583 represents a mutation. Formal proof of the mutation, however, will require functional analyses of the mutant protein.

The ABCG5 half-transporter was initially speculated to act as a heterodimer with the ABCG8 half-transporter, because mutations in sitosterolemia patients have been found exclusively in ABCG5 or ABCG8, but never together (5–7, 11, 12). Graf et al. (26) have now demonstrated that ABCG5 and ABCG8 are N-linked glycosylated, physically interact, and require one another for transport from the endoplasmic reticulum to apical membranes. Our missense mutation in the extracellular loop between transmembrane domains 5 and 6 occurs near the canonical N-glycosylation sites of sterolin-1. We speculate that the amino acid substitution, which results in the addition of a sulfhydryl group, alters the tertiary structure of the protein, thereby preventing its interaction with sterolin-2. Consequently, assembly of the heterodimer and subsequent translocation from the endoplasmic reticulum into plasma/apical membranes will not occur, resulting in complete loss of ABC transporter function; however, one cannot rule out the possibility that the mutant ABC transporter may be properly expressed in plasma/apical membranes and still not function. Because expression of human ABCG5 and ABCG8 in mice caused a marked reduction in plasma levels of plant sterols (8), a loss of transporter function may lead to increased retention of plant sterols, presenting as phytosterolemia. Therefore, it appears that the SHR and SHRSP rat strains are excellent animal models for hypertension, hemorrhagic stroke, and phytosterolemia. Our results demonstrate that WKY inbred, SHR, and SHRSP rat strains represent the first naturally occurring animal models for the human disorder sitosterolemia, and are important models for studying the mechanisms of sterol trafficking..


   ACKNOWLEDGMENTS
 
The authors thank Dr. Nimal Ratnayake and Dr. Dennis Bulman for insightful discussions and Drs. Nimal Ratnayake, Steve Brooks, Jesse Bertinato, Kevin Cockell, Mary L'Abbé, Fraser Scott, and the Animal Resource Division at Health Canada for providing rat tissue samples. This research was funded by Health Canada.

Manuscript received November 13, 2002 and in revised form February 14, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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