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(Investigative Ophthalmology and Visual Science. 2001;42:3123-3129.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Organization of the Human IMPG2 Gene and Its Evaluation as a Candidate Gene in Age-Related Macular Degeneration and Other Retinal Degenerative Disorders

Markus H. Kuehn, Edwin M. Stone and Gregory S. Hageman

From the Department of Ophthalmology and Visual Sciences, The University of Iowa Center for Macular Degeneration, Iowa City.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To characterize the genomic organization of human IMPG2, the gene encoding the retinal interphotoreceptor matrix (IPM) proteoglycan IPM 200, to evaluate its relationship to IPM 150, and to evaluate its involvement in inherited retinopathies, such as age-related macular degeneration, retinitis pigmentosa, and Leber congenital amaurosis.

METHODS. After isolation of human genomic clones, the structure of IMPG2 was determined by sequence analysis. Mutational analyses were conducted on genomic DNA isolated from 316 probands using single-strand conformation polymorphism analysis.

RESULTS. The IMPG2 gene is organized into 19 exons, and the structure of the gene is highly similar to that of the IMPG1 gene, which encodes another retinal proteoglycan, IPM 150. Mutational analyses indicate that the observed sequence changes are present at approximately equal rates in donors with and without retinal disease. Additional data derived from RT-PCR and Northern blot analysis show that IMPG2 is processed in the human retina into multiple alternatively sized transcripts that may represent splicing isoforms.

CONCLUSIONS. Analysis of the overall relationship of human IMPG2 (located on chromosome 3q12.2-12.3) to human IMPG1 (located on chromosome 6q14) suggests that these genes have evolved from a common ancestral gene. Although this is an excellent candidate gene for hereditary retinopathies, single-strand conformation polymorphism analyses provided no evidence that variations in IMPG2 coding region are responsible for the inherited retinopathies examined.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In previous studies, we have identified and characterized two novel human interphotoreceptor matrix (IPM) proteoglycans, designated IPM 2001 2 and IPM 1501 3 4 5 that, together with their associated isoforms, comprise a unique family of extracellular proteins. These molecules were initially identified as constituents of the IPM, an extracellular matrix that surrounds retinal photoreceptor outer segments and ellipsoids.1 Other reports suggest that IPM 200 may also be expressed in nonocular tissues, including the brain.6 7

The IPM is crucial for normal function and viability of retinal photoreceptor cells. It is a likely participant in the exchange of metabolites and catabolic byproducts between the retinal pigment epithelium and photoreceptor cells, the regulation of the subretinal ionic milieu, and the orientation, polarization, and turnover of photoreceptor outer segments.8 9 10 11 12 IPM proteoglycans have been shown to mediate photoreceptor cell adhesion.13 14 15 16 IPM 200 and IPM 150 may also mediate photoreceptor cell survival by sequestration of growth factors10 17 or through the epidermal growth factor (EGF)-like domains contained within their core proteins.2 3 5

Photoreceptor cells are highly vulnerable to dysfunction and/or death in various heritable retinal dystrophies and degenerations (reviewed in Ref. 18 ). Nucleotide sequence variations in the genes encoding a number of retinal proteins are associated with the etiologies of various forms of retinal degeneration. For example, mutations in the genes encoding retinal rhodopsin, ß-phosphodiesterase, rab geranylgeranyl transferase, rim protein, and the RP1 gene product cause retinal degeneration.19 20 21 22 23

Because IPM 200 is expressed at high levels by retinal photoreceptor cells and probably plays a critical role in the maintenance of the interphotoreceptor space, it is reasonable to postulate that sequence variations within its gene, IMPG2, may cause photoreceptor cell dysfunction and/or retinal degeneration. The IMPG2 gene has been mapped to chromosome 3q12.2-12.3 between markers WI3277 and NIB1880.2 Although no human hereditary diseases have yet been mapped to this interval, IMPG2 is a strong candidate gene for unmapped inherited ocular, or neuronal, disorders, including age-related macular degeneration (AMD).

AMD is a significant cause of irreversible blindness worldwide. There is strong evidence that a significant proportion of AMD has a genetic foundation,24 25 26 27 and several AMD loci have been identified.28 29 In addition, the ApoE4 allele has been shown to be protective for the disease.30 In this study we screened DNA from patients with abnormalities on both sides of the photoreceptor cell–retinal pigment epithelium interface with a wide range in age of onset, from birth to the ninth decade of life, for mutations in IMPG2. These afflictions include AMD, retinitis pigmentosa (RP), and Leber congenital amaurosis (LCA)—three genetically heterogeneous retinal diseases characterized by photoreceptor cell death.31 32 33


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Identification and Characterization of Genomic Subclones
To identify bacterial artificial chromosome (BAC) clones that contain portions of the IMPG2 gene, several PCR primer pairs were generated based on the IPM 200 cDNA sequence (GenBank accession no. AF173155; GenBank is provided by the National Center for Biotechnology Information and available in the public domain at http://www.ncbi.nlm.nih.gov/genbank). Two of these primer pairs (sense 1: 5'-AAA AAG AAA CAG CCT CTG GAC CGC AG-3' and antisense 1: 5'-CAG CCT CTG CAA CAC TTT CAT CTG GG-3', spanning nucleotides 372 to 492 of the IPM 200 cDNA; sense 2: 5'-TCA TTC ACT CAA CCT GTG C-3' and antisense 2: 5'-GAC CCT GAA CCT AAA CCA C-3', spanning nucleotides 1794 to 2005 of the IPM 200 cDNA) consistently yielded PCR amplification products of the expected size when human genomic DNA was used as a template. These primer pairs were used to screen a commercially available human BAC library (Genome Systems, St. Louis, MO). BAC clones 340M10, 366H07, 325H22, and 493P03 appeared to contain portions of the IMPG2 gene. The human genomic DNA was isolated from these BAC clones and fragmented by digestion with the restriction endonucleases HindIII, SacI, or EcoRI. The resultant fragments were ligated into either dephosphorylated vector pBluescript SK (Stratagene, La Jolla, CA) or pClonesure (CPG Inc., Fairfield, NJ) without further purification. After transformation by electroporation, Escherichia coli TOP 10 cells were grown overnight, at 37°C, on Luria-Bertani (LB) broth–based agar plates containing carbenicillin (50 µg/ml). From each restriction digest, 48 subclones were randomly selected and arrayed into 96-well microtiter plates. To identify subclones containing specific regions of IMPG2, nitrocellulose membranes were placed on LB-agar plates containing carbenicillin, and a small number of cells from each subclone were transferred to establish colonies directly on the membranes. Colonies were grown overnight at 37°C. DNA bound to the filter was then denatured by incubation in 0.5 M NaOH and 1.5 M NaCl for 5 minutes, neutralized in 1 M Tris (pH 8.0) and 1.5 M NaCl for 5 minutes, briefly rinsed in 2x SSC, and cross-linked to the membranes using UV irradiation. The filters were then incubated overnight in hybridization buffer containing 32[P]-labeled oligonucleotides that were designed based on the human IPM 200 cDNA sequence. After removal of unbound probe, filters were exposed to x-ray film to identify subclones yielding hybridization signals.

Plasmids were isolated from these colonies and sequenced. Exonic domains were determined by comparison of the obtained genomic sequences to that of the cDNA sequence.

Human Subjects
The study included 92 individuals with AMD, 92 with RP, 40 with LCA, and 92 normal individuals (control subjects). The control subjects were between the ages of 44 and 93 and were not afflicted with any ocular diseases. All probands with AMD and all control subjects were ascertained at The University of Iowa Hospitals and Clinics, whereas portions of the RP and LCA groups were ascertained at other centers. The protocol was in compliance with the tenets of the Declaration of Helsinki.

Single-Strand Conformation Polymorphism Analyses
Genomic DNA from each study participant was screened for sequence variations in the IPM 200 coding sequence by single-strand conformation polymorphism (SSCP) analysis. PCR amplification reactions (10 µl) contained 5 ng human genomic DNA, 10 ng each PCR primer, 2.5 mM MgCl2, 0.25 U Taq polymerase, and 1x Taq polymerase buffer. Occasionally, reaction conditions were varied slightly to achieve optimal amplification when using specific primer pairs (Table 1) . These variations included the addition of 10% dimethyl sulfoxide (DMSO), the use of 1.5 mM MgCl2 instead of 2.5 mM MgCl2, or the use of "touchdown" PCR. All samples generally underwent 35 cycles of amplification and were then diluted with one volume of sample buffer (95% formamide, 20 mM EDTA, 0.05% xylene cyanol green and 0.05% bromophenol blue). Samples were heat denatured, electrophoresed on 6% nondenaturing polyacrylamide gels and visualized by silver staining, as described previously.34 Samples of exons exhibiting band shifts were amplified again, purified, and sequenced bidirectionally on an automated DNA sequencer (model 377; PE Applied Biosystems, Foster City, CA).


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  		Table 1. PCR Primers used during SSCP Analyses of the IMPG2 Gene

 
RT-PCR Analyses
Total retinal RNA was isolated from human donor tissue within 4 hours after death using spin columns (RNeasy; Qiagen, Valencia, CA). The RNA was reverse transcribed using random hexamer primers and reverse transcriptase (SuperscriptII; Gibco BRL, Grand Island, NY). Fifty nanograms of the resultant single-stranded cDNA was PCR amplified using primers designed based on the human IPM 200 cDNA sequence. The derived PCR fragments were analyzed by electrophoretic separation on agarose gels. The primers used to amplify the open reading frame of human IPM 200 were sense, 5'-TTGGAAGTTT CAAGGATTTG-3', and antisense, 5'-AACACAGCAT TCAGTCTTTA TAG-3'. The expected 4017-bp amplification product of spans between bp 120 and bp 4135 (exons 1 and 19, respectively) of the previously published IPM 200 cDNA sequence (GenBank accession no. AF173155).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Genomic Organization of the IMPG2 Gene
The intron–exon boundaries of the IMPG2 gene and portions of the intronic sequences flanking the exons were determined by partially sequencing four overlapping BAC clones (Fig. 1) . The IMPG2 gene comprises 19 exons ranging in size between 21 and 1259 bp. The 5' and 3' ends of all exons exhibited sequences that were consistent with consensus acceptor and donor splice sites, respectively (Table 2) . These sequences have been deposited in GenBank (accession numbers AF271363 through AF271379). Summation of all nonoverlapping sequences obtained in the course of this study indicated that the gene is at least 31.0 kb in size. In addition, approximately 700 bp of genomic sequence located immediately upstream of the IMPG2 gene were determined.



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  		Figure 1. Organization of the IMPG2 gene and the BAC contig used to determine it. Broken lines: intronic regions that were not completely sequenced.

 

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  		Table 2. Exon–Intron Junctions of the Human IMPG2 Gene

 
Comparison of the Organization of IMPG2 and IMPG1
As reported earlier, comparison of IPM 200 and IPM 150 cDNAs and their deduced amino acid sequences indicated that the two proteins are closely related to one other and constitute a novel family of glycoproteins.2 5 Analyses of the genomic organization of their respective genes, IMPG2 and IMPG1, support these data. Alignment of the human IPM 150 and IPM 200 amino acid sequences revealed that the size, distribution and overall organization of exons is highly conserved between the two genes (Fig. 2) . Closer analysis indicated that regions of high amino acid sequence conservation correspond directly to regions in which the genomic organization is more stringently preserved. In regions of the genes that encode the more highly conserved amino- and carboxyl-terminal regions of the IPM 150 and IPM 200 proteins, the intron–exon boundaries often occur precisely at the same amino acid (Fig. 3) . The conservation of genomic structure is less stringent in the regions that encode the central domains of the IPM 150 and IPM 200 proteins. These are the same regions in which the primary structures of the proteins are also less conserved.



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  		Figure 2. Organization and comparison of the IMPG2 (top) and IMPG1 (bottom) genes and their encoded proteins, IPM 200 and IPM 150. Black boxes: regions of high sequence homology; darkly shaded boxes: regions of moderate homology; lightly shaded boxes: regions of low sequence homology. Vertical lines: borders between exons; thin horizontal lines: insertion of gaps; ovals: EGF-like domains; diamond: hydrophobic, putative transmembrane domain of IPM 200.

 


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  		Figure 3. Alignment of the IPM 200 (top) and IPM 150 (bottom) core proteins. Arrows: exon boundaries.

 
Screening of IMPG2 in Patients with Retinal Disease
To assess the potential involvement of the IMPG2 gene in the development of AMD, LCA, and RP, we screened genomic DNA obtained from 224 patients affected with these retinopathies for sequence changes within the exons of this gene. The data obtained were compared with those derived from a group of 92 patients for whom there was no clinical evidence of retinal disease. Three sequence changes were identified in the coding region of the gene (Table 3) . A silent T->C transition in the third position of the codon for Leu1127 was observed in approximately 25% of both affected and unaffected individuals. Approximately one third of all evaluated alleles display a C->T change in exon 13, which induces a Thr674Ile change in the mucin-like domain of IPM 200. A rare C->T change, resulting in a Pro1013Leu substitution immediately preceding the first EGF-like domain, was observed in approximately 1% of AMD-affected and control individuals. In addition, an intronic A->G sequence change 10 bp downstream of exon 6 was observed in approximately 45% of all examined alleles. Thus, individuals from both the affected and control groups harbored all observed sequence variations at approximately equal rates, suggesting that the detected base changes represented nondisease-causing polymorphisms.


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  		Table 3. Allelic Distribution of the Observed Polymorphic Markers in the Human IMPG2 Gene

 
Identification of Alternative Transcripts of Human IPM 200
Several bands running at a molecular weight lower than 6.2 kb were observed on extended autoradiographic exposure of Northern blot analysis of retinal RNA hybridized with IPM 200 cDNA probes (Fig. 4B) . These data indicate the presence of transcripts of several sizes, suggesting that various splicing isoforms of IPM 200 may exist. To confirm these data and to rule out that the additional observed bands are due to alternative initiation of transcripts or polyadenylation, RT-PCR amplification of IPM 200 from human retinal cDNA was performed. RT-PCR of the open reading frame of human IPM 200 produced the 4.0-kb amplification product predicted from the previously described cDNA sequence, as well as several smaller PCR products of approximately 3.7, 3.6, 2.9, and 1.8 kb (Fig. 4A) . These findings demonstrate that the observed transcripts differ within the coding region of the cDNA, resulting in all likelihood in the synthesis of several distinct protein isoforms.



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  		Figure 4. RT-PCR (A) and Northern blot (B) analyses of IPM 200 expression in the human retina and RPE-choroid (RPE/Ch). Arrows: alternatively sized transcripts of IPM 200.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this report, we describe the organization of the human IMPG2 gene that encodes the prominent retinal proteoglycan IPM 200.2 4 Analyses of the IMPG2 gene, located on chromosome 3q12, indicate that it comprises 19 exons that span a minimum of 31.0 kb. A few sequence variations were identified in the IMPG2 gene after genetic analyses of individuals with RP, LCA, or AMD and unaffected control subjects. However, no significant partitioning of these polymorphisms between affected and unaffected individuals was detected. Hence, there are no indications that mutations in the coding region of IMPG2 are involved in the development of these three retinopathies. However, it is difficult to completely rule out the possibility that mutations in this gene may be involved in these retinal diseases, because certain types of mutations, such as genomic rearrangements, cannot be detected by SSCP. In addition, sequence changes in noncoding regions, such as 5' regulatory elements or splicing branch sites, may severely interfere with the functionality of the IMPG2 gene.

The exonic structures of IMPG2 and that of IMPG1, which encodes the related proteoglycan IPM 150,3 4 35 36 are remarkably well conserved based on alignment of the amino acid sequences and insertion of gaps to account for the difference in overall size of the proteins (Fig. 3) . Many exons are either of identical length or terminate in similar locations. These observations indicate that IPM 200 and IPM 150 are members of a single gene family. We speculate that the IMPG1 and IMPG2 genes may have arisen from the duplication of a single ancestral gene. Thus, it is conceivable that IPM 200 and IPM 150, at least in part, may be functionally redundant and that retinal dysfunction and/or degeneration occurs only if both proteins are defective.

Previous reports suggested that there are splicing isoforms of IPM 150 in the human retina.3 35 Based on the data presented herein, it appears that human retinal IPM 200 is also synthesized as several isoforms. The nature of these IPM 200 variants has not been elucidated, although the properties of individual isoforms of the same gene can be quite diverse. For example, tenascin-C splice variants differ only in the number of their fibronectin type III domains, yet some variants possess adhesive properties, whereas others display antiadhesive characteristics.37 38 39 Furthermore, it appears that the functional differences of the tenascin isoforms are in part dependent on their environment.40 By analogy, it is possible that isoforms of IPM 200 serve distinct functions. It is also conceivable that these isoforms are synthesized by specific photoreceptor cell types. Future studies should provide additional insight into the isoforms and functions of IPM 200.


   Acknowledgements
 
The authors thank Louisa Affatigato and Jake Roos for technical assistance, Val Sheffield, MD, Ph.D., and his staff for performing sequence analyses, and Robert Mullins, Ph.D., for helpful discussions throughout the project.


   Footnotes
 
Supported in part by National Eye Institute Grants EY06463 (GSH), EY11515 (GSH), and EY10539 (EMS); The Roy C. Carver Endowment for Molecular Ophthalmology (EMS); a Research to Prevent Blindness Lew R. Wasserman Merit Award (GSH); a National Research Service Award (MHK); and an unrestricted grant to the Department of Ophthalmology and Visual Sciences, University of Iowa, from Research to Prevent Blindness, Inc.

Submitted for publication April 6, 2001; revised July 30, 2001; accepted August 14, 2001.

Commercial relationships policy: P.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Gregory S. Hageman, The University of Iowa Center for Macular Degeneration, Department of Ophthalmology and Visual Sciences, The University of Iowa, 11190E PFP, 200 Hawkins Drive, Iowa City, IA 52242. gregory-hageman{at}uiowa.edu


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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