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Diverse Macular Dystrophy Phenotype Caused by a Novel Complex Mutation in the ELOVL4 Gene

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Diverse Macular Dystrophy Phenotype Caused by a Novel Complex Mutation in the ELOVL4 Gene Diverse Macular Dystrophy Phenotype Caused by a Novel Complex Mutation in the ELOVL4 Gene Paul S. Bernstein,1 Jaana Tammur,2,3 Nanda Singh,4 Amy Hutchinson,2 Missy Dixon,4 Chris M. Pappas,4 Norman A. Zabriskie,1 Kang Zhang,5 Konstantin Petrukhin,6 Mark Leppert,4 and Rando Allikmets2,7 PURPOSE. A 5-bp deletion in ELOVL4, a photoreceptor-specific flecks. Stargardt disease (STGD; Mendelian Inheritance in gene, has been associated with autosomal dominant (ad) mac- Man [MIM] 248200) can be inherited as an autosomal reces- ular dystrophy phenotypes in five related families, in which sive (ar) trait (MIM 248200) or an autosomal dominant (ad) phenotypes range from Stargardt-like macular dystrophy trait (MIM 600110; 603786). All recessive forms of STGD (STGD3; Mendelian Inheritance in Man 600110) to pattern have been linked to a locus on 1p32, containing the ABCR dystrophy. This has been the only mutation identified in (ABCA4) gene.1 Mutations in ABCR, a photoreceptor-spe- ELOVL4 to date, which is associated with macular dystrophy cific adenosine triphosphate (ATP)-binding cassette (ABC) phenotypes. In the current study, the potential involvement transporter, are causal in arSTGD2 and in a number of other was investigated of an ELOVL4 gene variation in adSTGD-like retinal diseases, such as recessive cone–rod dystrophy and other macular dystrophy phenotypes segregating in a large (CRD),3 and some forms of autosomal recessive retinitis unrelated pedigree from Utah (K4175). pigmentosa (RP19).4,5 Heterozygous carriers of ABCR vari- ETHODS ant alleles are more susceptible to age-related macular de- M . The entire open reading frame of the ELOVL4 gene 6,7 was analyzed by direct sequencing in a proband from the generation (AMD), a late-onset complex trait. Rare auto- K4175 family. The combination of denaturing high-perfor- somal dominant forms of STGD-like phenotypes have been mapped to several loci on the human genome, including mance liquid chromatography (DHPLC) analysis and direct 8 9 sequencing of all available family members was used to further those on chromosome 6q14 (STGD3) and 4p (STGD4). Recently, we cloned and characterized the gene responsible assess segregation of identified ELOVL4 variants in the pedi- 10 gree. for STGD-like macular dystrophy (STGD3) on 6q14. The protein, encoded by this photoreceptor-specific gene, elon- RESULTS. A complex mutation, two 1-bp deletions separated by gation factor of very-long-chain fatty acids (ELOVL4), prob- four nucleotides, was detected in all affected members of the ably performs an important function in the biosynthesis of family. The mutation results in a frameshift and the truncation photoreceptor outer segment membrane components. Af- of the ELOVL4 protein, similar to the effect of the previously fected members in all five families segregating the STGD3 or described 5-bp deletion. other macular dystrophy phenotypes harbored the same CONCLUSIONS. The discovery of a second mutation in the presumed founder mutation, 797-801delAACTT.10 This 5-bp ELOVL4 gene segregating with macular dystrophy phenotypes deletion causes a frameshift and premature termination of confirms the role of this gene in a subset of dominant macular the protein, strongly suggesting the pathogenic nature of dystrophies with a wide range of clinical expressions and this sequence change. Until now, screening of patients with suggests a role for modifying genes and/or environmental fac- AMD or additional families with autosomal dominant macu- tors in the disease process. (Invest Ophthalmol Vis Sci. 2001; lar dystrophy phenotypes has not revealed any other dis- 42:3331–3336) ease-associated ELOVL4 sequence variants11 to directly sup- port the previous conclusion. In the current study, we targardt macular dystrophies are a collection of early- investigated the potential involvement of ELOVL4 gene vari- S onset disorders characterized by macular atrophy sur- ation in adSTGD-like and other macular dystrophy pheno- rounded by lipofuscin-containing orange-yellow fundus types segregating in a large pedigree from Utah. MATERIALS AND METHODS From the 1Department of Ophthalmology and Visual Sciences, Moran Eye Center, and the 4Department of Human Genetics, Eccles Recruitment of Subjects Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah; the Departments of 2Ophthalmology and 7Pathol- A large family with apparent autosomal dominant macular dystrophy ogy, Columbia University, New York, New York; the 3Department of was identified from the clinic population of the Moran Eye Center of Biotechnology, Institute of Molecular and Cell Biology, Tartu Univer- the University of Utah. Complete eye examinations, including best sity, Estonia; the 5Cole Eye Institute, Cleveland Clinic Foundation, corrected visual acuity, dilated fundoscopy, and color fundus photog- 6 Cleveland, Ohio; and the Department of Pharmacology, Merck Re- raphy were performed, and blood was collected from all available search Laboratories, West Point, Pennsylvania. family members who were able to come to Salt Lake City. Selected Supported by Grants EY-11600, EY-11309, and EY-13435 from the individuals had digital fluorescein angiograms recorded (Imagenet; National Institutes of Health, Bethesda, Maryland; by grants from the Foundation Fighting Blindness and Research to Prevent Blindness; and Topcon Optical, Tokyo, Japan) system. Family members unable to by the Steinbach Fund, New York, New York. come to Salt Lake City had examinations, photography, and blood Submitted for publication June 1, 2001; revised August 22, 2001; collection performed by their local ophthalmologists. All participants accepted September 5, 2001. signed institutionally approved consent forms, and recruitment and Commercial relationships policy: N. research procedures complied with the tenets of the Declaration of The publication costs of this article were defrayed in part by page Helsinki. charge payment. This article must therefore be marked “advertise- ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Mutation Detection by Direct Sequencing Corresponding author: Rando Allikmets, Department of Ophthal- mology, Columbia University, Eye Research Addition, Room 715, 630 DNA samples from two first-cousin family members (III-1 and III-7) West 168th Street, New York, NY 10032. [email protected] were analyzed for ELOVL4 variants by direct sequencing. Each exon of Investigative Ophthalmology & Visual Science, December 2001, Vol. 42, No. 13 Copyright © Association for Research in Vision and Ophthalmology 3331 3332 Bernstein et al. IOVS, December 2001, Vol. 42, No. 13 FIGURE 1. K4175 pedigree and segregation of genotypes. (A) Filled circles and squares: affected females and males, respectively; stippled circles and squares: nonpenetrant females and males, respectively; open circles and squares: unaffected females and males, respectively. Below each individual are genotypes as determined by the dinucleotide marker D6S460 and the combination of DHPLC and direct-sequencing information from the ELOVL4 locus for the two, single-nucleotide deletions (ELOVL4del) or wild type (ϩ) and the methionine (M) to valine (V) polymorphism (M299V) in exon 6 of ELOVL4. The disease chromosome is boxed. Affected status of deceased individuals was determined by reports from living family members. (B) DHPLC profiles for the four possible combinations of ELOVL4 alleles in exon 6. The homozygous ϩ/ϩ; V/V genotype in individual III-2 is indistinguishable from the wild-type ϩ/ϩ; M/M by DHPLC and so was determined by direct sequencing. the ELOVL4 gene was amplified by PCR with previously described analysis was performed for exon 6 of ELOVL4 on 292 healthy control primers,10 and sequencing was performed according to the manufac- individuals and on 513 patients with diagnosed AMD. One DNA sample turer’s protocols (Model ABI 377; PE Biosystems, Foster City, CA). from each group was included on every run as a positive control (a Similarly, all exons of the ABCA4 and peripherin/RDS genes were representative of a specific genotype). If a sample deviated from any of directly sequenced with previously published primer pairs.2 the controls, indicating a different genotype, it was directly sequenced as described earlier. Subcloning of ELOVL4 Alleles The sequence of mutant ELOVL4 alleles was determined directly from Linkage Analysis the chromatograms of heterozygous samples. To further demonstrate the exact sequence of individual ELOVL4 alleles in exon 6 in patient DNA was isolated from venous blood as has been described. For III-1, the gel-purified PCR product was cloned into pCR2.1-TOPO linkage analysis, DNA was amplified under the following conditions: vector using a cloning system (Topo TA Cloning; Invitrogen, San 100 to 200 ng DNA, 1.5 mM Mg PCR buffer, 200 ␮m dNTPs, 4% Diego, CA) according to the manufacturer’s protocol. Twelve individ- dimethyl sulfoxide (DMSO), 10 pmol primer, (forward primer end- ual clones were picked for sequencing, which was performed as labeled with ␥-ATP, using T4 polynucleotide kinase; Molecular Biology described earlier. Resources, Milwaukee, WI), and 1 U Taq polymerase (Roche Molecular Biochemicals, Indianapolis, IN), in a 25-␮l reaction at 94°C for 5 Segregation Analysis by Denaturing High- minutes; 8 cycles of 94°C for 20 seconds, 64°C for 20 seconds less Performance Liquid Chromatography 1°/cycle, and 72°C for 40 seconds; followed by 23 cycles of 94°C for DNA of all available members of the K4175 pedigree was PCR ampli- 20 seconds, 56°C for 20 seconds, 72°C for 40
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