Human Molecular Genetics, 2000, Vol. 9, No. 13 2051-2058
© 2000 Oxford University Press
Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome)
Department of Biology, University of São Paulo, Rua do Matão 277, 05508-900 São Paulo, Brazil, 1Institute of Medical Genetics, Catholic University, Rome, Italy and 2Ludwig Institute for Cancer Research, São Paulo, Brazil
Received 25 April 2000; Revised and Accepted 23 June 2000.
DDBJ/EMBL/GenBank accession no. AJ239326.
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ABSTRACT |
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Knobloch syndrome (KS) is an autosomal recessive disorder defined by the occurrence of high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele. The KS causative gene had been assigned to a 4.3 cM interval at 21q22.3 by linkage analysis of a large consanguineous Brazilian family. We reconstructed the haplotypes of this family with ten additional markers (five were novel) and narrowed the candidate interval to a region of <245 kb, which contains 24 expressed sequence tags, the KIAA0958 gene and the 5' end of the COL18A1 gene. We identified a homozygous mutation at the AG consensus acceptor splice site of COL18A1 intron 1 exclusively among the 12 KS patients, which was not found among 140 control chromosomes. This mutation predicts the creation of a stop codon in exon 4 and therefore the truncation of the
1(XVIII) collagen short form, which was expressed in human adult retina. These findings provide evidence that KS is caused by mutations in COL18A1 which, therefore, has a major role in determining the retinal structure as well as in the closure of the neural tube. Therefore, we show for the first time that the absence of a collagen isoform impairs embryonic cell proliferation and/or migration as a primary or secondary effect. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Knobloch syndrome (KS) is an autosomal recessive disorder defined by the occurrence of high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele (1–6). Clinical variability is present in the manifestation of this syndrome, but all patients invariably have ocular abnormalities, which are severe, progressive and irreversible, leading to bilateral blindness. The occipital encephalocele is also a major clinical feature, as it has been described in 22 of 24 reported cases; however, there is considerable controversy concerning its classification as scalp defect or true encephalocele. Other minor clinical abnormalities, such as lens subluxation, cataracts, hypoplasia of the right lung with anomalous pulmonary return, cardiac dextroversion, flat nasal bridge, midface hypoplasia, bilateral epicanthic folds, generalized hyperextensibility of the joints, unilateral duplicated renal collecting system and unusual palmar creases, have been observed in single families (Table 1) (1–6). It is still unclear whether these features are part of the clinical spectrum of this syndrome. Interestingly, the ocular alterations of patients with KS are very similar to the ones described in Stickler, Wagner and Marshall syndromes, as well as in erosive vitreoretinopathy (7–11). Most Stickler patients who show ocular changes have been associated with mutations in the COL2A1 and COL11A1 genes (11–13). Wagner and Marshall syndromes can be allelic variants of Stickler syndrome, and erosive vitreoretinopathy and some families with Wagner syndrome are mapped to 5q13–q14 (10,11,14,15); however, there is still uncertainty about additional genetic heterogeneity for all these conditions. The partial clinical overlap between these type II and XI collagenopathies and KS suggests that the latter may also be caused by mutations in a collagen gene, as previously suggested by us (16). The identification of the gene underlying KS will be of utmost importance not only to elucidate the pathogenesis of this disorder, but also to clarify the question of genetic heterogeneity for all these phenotypes.
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We previously assigned the KS locus to a 4.3 cM region between D21S171 and D21S1446 on chromosome 21q22.3 through linkage analysis of a large Brazilian family (16). Here we report the restriction of the critical interval harboring the KS gene from 2.5 Mb to 245 kb. Two known genes lie in this interval: KIAA0958 and the 5' end of COL18A1. The KIAA0958 gene consists of seven exons and encodes a 428 residue protein which shows 36.8% identity with a protein of Caenorhabditis elegans and 35.7% identity with a protein of Drosophila melanogaster, all of them with unknown function (17). The COL18A1 gene includes 43 exons and is transcribed in two variant spliced isoforms: (i) a short mRNA variant, including exons 1, 2 and 4–43 and encoding a 1336 residue chain; and (ii) a long variant containing exons 3–43 and encoding a 1516 residue chain (18). Through a positional candidate approach we identified the COL18A1 gene as being responsible for the etiology of KS. These findings provide evidence that the short
1(XVIII) collagen has a major role in determining the retinal structure as well as in the closure of the neural tube. In addition, we showed for the first time that the absence of a collagen isoform impairs embryonic cell proliferation and/or migration. |
RESULTS |
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The chromosomal interval defined for KS
We genotyped a Brazilian family for five additional known markers: (cen) D21S1897, COL18A1/3'-untranslated region (3'-UTR), D21S112, COL6A2 and D21S1575 (tel). The first four markers are mapped between the two previously defined flanking markers for the KS locus, D21S171 and D21S1446; whereas the marker D21S1575 is distal to D21S1446. Based on two critical recombinants, patient V-9 and individual III-5, we placed the KS gene between D21S1897 and COL18A1/3'-UTR (Fig. 1), restricting the KS interval from 2.5 Mb to <400 kb.
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The loci ADARB1, KIAA0958 and COL18A1 lie within this new candidate interval (cen
tel) (19). Detailed analysis of these genes and of the genomic sequence of 21q22.3 (now available as part of the chromosome 21 sequencing project) allowed us to identify two polymorphic systems at the 3'-UTR of ADARB1, two single nucleotide polymorphisms (SNPs) located within introns 6 and 17 of COL18A1 and one polymorphic repeated region (61300), 9.5 kb distal to ADARB1 and 40 kb proximal to KIAA0958 (Table 2).
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Subsequently, we genotyped the KS family with these new markers (Fig. 1). We observed that patient V-9, who previously defined the proximal border of the candidate area, was also recombinant for the ADARB1 polymorphisms and 61300; in addition, the individual III-5, who defined the distal border, was also recombinant for the SNPs within introns 6 and 17 of COL18A1. Therefore, these informative recombination events allowed the exclusion of ADARB1 and most of the COL18A1 gene (exons 7–43) as candidates, reducing the chromosomal critical region to <245 kb. This region contains 24 expressed sequence tags (ESTs), the KIAA0958 gene and the 5' end of the COL18A1 gene (Fig. 2).
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KIAA0958 and COL18A1 mutation analysis
To search for KIAA0958 gene mutations we analyzed its seven exons and their intron boundaries in KS patients. We did not find any disease-causing mutations, excluding it as a candidate for this syndrome.
We subsequently analyzed the 5' region of the COL18A1 gene in the Brazilian family. We identified an AT transversion in the canonic acceptor splice site of COL18A1 intron 1 (IVS1–2AT) (Fig. 3). This substitution co-segregates with the disease phenotype in the family without exception: it was present in homozygosity in all 12 affected patients and in heterozygosity among the obligate carriers of the disease allele (based on haplotype and/or genealogy analysis), whereas it was not found in 140 chromosomes from healthy individuals of the Brazilian population. Thus, the splice site mutation observed in these KS patients affects only the 1(XVIII) short isoform.
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Interestingly, all alleles carrying the A
T transversion also had a CG substitution 115 bp dowstream of the gt donor splice site of intron 2 (IVS2+115CG) which was also not found in control individuals.
Expression studies of variant COL18A1 mRNAs
We re-evaluated the expression of the two COL18A1 variant mRNAs in human fetal brain, placenta and skin fibroblast and analyzed for the first time their expression in human adult retina and lymphocytes. We verified that the short isoform was only expressed in retina, fetal brain and placenta. In contrast, we were unable to amplify the longer isoform in any of the tissues tested (Fig. 4).
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DISCUSSION |
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Our study provides evidence that a mutation at the acceptor splice site of COL18A1 intron 1 (IVS1–2A
T) causes KS, confirming our previous hypothesis that this disease belongs to the group of collagenopathies. All of the COL18A1 introns have the conventional gt-ag donor and acceptor splice sites; moreover, the 3' splice junction of intron 1 is conserved between human and mouse (20). These observations support the hypothesis that any mutation at this canonic splice site is pathogenic. The IVS1–2AT mutation is expected to result in exon 2 skipping and in the creation of a premature termination codon within exon 4 of the COL18A1 transcript (Fig. 5). Therefore, KS patients should be deficient for only the 1(XVIII) collagen short chain, since exon 2 is transcribed only in this isoform. On the other hand, the substitution IVS2+115CG is not expected to be pathogenic as it does not create any potential splice site, and may represent a rare allele in linkage disequilibrium with the disease mutation.
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Type XVIII collagen is a heparan sulfate proteoglycan of the extracellular matrix, which together with the non-fibrillar type XV collagen forms a novel subclass of the collagen superfamily (subgroup of multiplexins, multiple triple domains with interruptions) (21,22). It has been reported previously that both in mouse and human, the long mRNA variant is mainly expressed in fetal and adult liver, and the short variant was found with the highest levels in fetal and adult kidney (18,20–24). Interestingly, the short isoform was found to be a ubiquitous basement membrane component, occurring prominently at vascular and epithelial basement membranes throughout the body (23,24). The expression pattern and tissue distribution of type XVIII collagen in chicken embryo are similar to that in mouse and human; in addition, this collagen was also detected in chicken retina (25). Here we demonstrate that the COL18A1 short variant is expressed in human retina and fetal brain, which are the tissues almost invariably affected in KS patients.
The two 1(XVIII) chains differ at the signal peptides and have variant N-terminal non-collagenous domains (NC1), which are 303 and 493 residues in length, respectively; and, therefore, the two chains share the last 301 residues of their NC1 regions, a 688 residue collagenous sequence (COL1–COL10) with nine interruptions, and a 312 residue C-terminal non-collagenous domain (18). Several putatively biologically important motifs have been described within the common region between the two isoforms, raising the possibility that the collagen XVIII proteins have more than one function. The last 184 residues of the C-terminal part correspond to a 20 kDa proteolytic fragment, called endostatin, which inhibits angiogenesis and tumor growth (26). The shared NC1 domain has a thrombospodin sequence motif, a glycoprotein with affinity for several molecules, but of still unknown significance. The COL8 domain has the Arg-Gly-Asp (RGD) site, also conserved in mouse, which is a possible binding site for integrins and, therefore, may play a role in cell attachment (18,27). However, it was experimentally shown in chicken that 1(XVIII) collagen has only modest adhesion-promoting activity for Schwann cells, indicating that this collagen does not act as a dominant cell adhesion protein and might have another function (25). Our finding of a mutant short variant associated with occipital encephalocele provides, for the first time, a clue for a specific function of this isoform, suggesting that it might play an important role in brain cell migration and/or proliferation.
This collagen isoform also seems to be critical for maintenance of the retinal structure as vitreoretinal degeneration, usually accompanied by retinal detachment, was observed in all KS patients (Table 1) (1–6). It is known that mutations in the COL2A1 and COL11A1 genes have been associated with Stickler, Wagner and Marshall syndromes (11–15). The polypeptides encoded by COL2A1 and COL11A1, together with 1(V), are the major fibrillar collagens of the extracellular matrix of the mammalian vitreous (28,29). Therefore, we suggest that the 1(XVIII) collagen short isoform may interact with these fibrillar collagens, contributing to the maintenance of the extracellular matrix of the retina. Indeed, non-fibrillar collagens (types IX, XII and XIV) can associate with fibrillar collagens to form fibers and fibrils (30). The prominent occurrence of the short isoform at vascular basement membranes throughout the body and the findings that endostatin inhibits angiogenesis (23,24,26,31,32), raise the possibility that the vitreoretinal degeneration and occipital encephalocele in KS patients may be a consequence of an inadequate vascularization of these tissues. It is intriguing that ocular anomalies and occipital encephalocele are the only clinical major alterations observed in our patients in spite of the ubiquitous presence of the collagen XVIII short isoform throughout the body. These observations, together with the lack of expression of the long isoform in retina and brain, suggest that the short variant plays a specialized function in these tissues.
Most of the other patients diagnosed with KS present additional mild morphological abnormalities (Table 1). It is possible that these cases have mutations in the region common to both 1(XVIII) collagen isoforms, which would explain some of their clinical features. Recently, a patient with mild line scalp defect of the frontal region associated with high myopia, vitreoretinal degeneration and abnormal macular pigmentation was diagnosed as having KS (6). The range of pathological phenotypes of KS will be expanded if a mutation in COL18A1 is identified in this patient.
It is intriguing that only one of six families with KS so far reported in the literature has consanguinity, which is lower than expected for a very rare autosomal recessive disease. Mutation screening of COL18A1 in patients with typical KS features, as well as in those with only some of the clinical characteristics of this syndrome, such as high myopia, will be important to delineate the spectrum of clinical variability of KS. Identification of other mutations will also contribute to a better understanding of the most functionally important regions of this collagen gene. In addition, it would also be important to develop mouse models in order to provide further information on Col18a1 gene functions and the mechanism underlying the pathogenesis of the disorder, even though it has been reported that mice homozygous for Col18a1 knockout alleles have developed normally, without evidence of abnormal vascular morphogenesis (26). It would be valuable to know whether O’Reilly et al. (26) performed eye examinations in these animals.
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MATERIALS AND METHODS |
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Family
The complete genealogy of the Brazilian KS family studied, including the clinical data, was reported previously (4). DNA samples are available from 12 affected and 17 normal individuals.
Genotyping analysis with previously reported polymorphic markers
We used the following polymorphic DNA markers: the microsatellites D21S1897 (33), COL6A2 (within intron 10 of the COL6A2 gene) (34), and D21S1575 (35); the VNTR D21S112 (36); and the three allele polymorphism at the 3'-UTR of the COL18A1 gene (37), designed here as the COL18A1/3'-UTR polymorphism.
The microsatellites were analyzed by PCR, performed in 10 µl (total volume) containing 40–60 ng of genomic DNA, 2.5 pmol of each primer, 200 µM dATP, dTTP, dGTP, 2.5 µM dCTP, 7.5 x 10–4 µCi [-32P]dCTP, 10 mM Tris–HCl pH 9.0, 50 mM KCl, 1.5 mM MgCl2, 0.01% gelatin, 0.1% Triton and 0.1 U Taq DNA polymerase (Gibco BRL, Rockville, MD). The thermocycling conditions used for amplification consisted of 28 cycles at 94°C for 30 s, 55°C for 30s and 72°C for 30s.
The PCR fragment derived from primer D21S112 was used to probe conventional Southern blots containing RsaI digests of 5 µg of genomic DNA. The probe was -32P-labeled using random priming (Amersham, Uppsala, Sweden) and subsequently purified using G-50 Sephadex columns. Hybridization was performed using standard conditions.
The COL18A1/3'-UTR polymorphism was performed by PCR and single-stranded conformation polymorphism (SSCP) analysis on the Brazilian family members according to published instructions (37).
Polymorphism screening
To identify new polymorphims within ADARB1, two different regions from the 3'-UTR of the gene (of 333 and 360 bp, named markers ADARB1A and ADARB1B, respectively), were PCR amplified from genomic DNA of 10 unrelated control individuals, and submitted to SSCP analysis according to standard protocols using 0.5x MDE gel solution (FMC BioProducts, Rockland, ME). We identified three different migrating SSCP patterns for each of the ADARB1 regions analyzed (ADARB1A and ADARB1B). Through sequence analysis, we verified that each SSCP variant was due to single base pair substitutions at two distinct positions in the same PCR product. Therefore, three distinct haplotypes (named 1, 2 and 3) were recognized for ADARB1A and three others for ADARB1B. Haplotype frequencies were calculated through SSCP analysis of 80 chromosomes from unrelated healthy Caucasians.
To identify new polymorphims within the COL18A1 gene, introns 6–8, 17–18 and 29–34 of the gene were also PCR amplified from genomic DNA of 10 unrelated control individuals, and submitted to SSCP analysis. Mobility shifts were detected in introns 6 and 17, and sequence analysis was carried out to characterize each of them. The SNP identified within intron 6 did not create a restriction site, and was tested further in 80 Caucasian chromosomes by SSCP analysis. The sequence alteration in intron 17 created a restriction site for Sau96AI, and PCR–restriction fragment length polymorphism (RFLP) analysis was performed to screen 80 Caucasian chromosomes for the presence of this mutation.
The primer pair used to amplify these regions was designed according to the available genomic sequence of 21q22.3. Mutations were described according to the nomenclature of Antonarakis et al. (38).
PCR was performed in 25 µl (total volume), containing 100 ng of genomic DNA, 20 pmol of each primer, 200 µM of each dNTP, 10 mM Tris–HCl pH 9.0, 50 mM KCl, 1.5 mM MgCl2, 0.01% gelatin, 0.1% Triton and 0.3 U Taq DNA polymerase (Gibco BRL). The conditions for the reaction were: 94°C for 4 min, 35 cycles at 94°C for 40 s, 55–60°C for 40 s, 72°C for 40 s, and a final extension of 72°C for 6 s.
We also amplified a repeated region (CAGGCGGAAGCGG)n which mapped 9.5 kb distal to ADARB1 and 40 kb proximal to KIAA0958 using the primer pair named 61300 (Table 2). The PCR conditions were the same as those used in the analysis of the other microsatellites.
EST database searching
We performed dbEST searches in the available genomic sequence of the candidate region using BLAST version 2.
Mutation analysis of the KIAA0958 and COL18A1 genes in KS patients
Seven exons of the KIAA9958 gene and exons 2–6 of the COL18A1 gene (and all its flanking intronic boundaries) were screened for mutations using SSCP analysis and bi-directional sequencing of all PCR products. The primer pairs used were designed on the basis of the genomic sequence of these genes, and are available on request. PCR conditions for genomic amplification were the same as those used in the identification of new polymorphic sequences. The sequence variation IVS2+115CG resulted in the creation of an ApaI restriction site and was confirmed by PCR–RFLP analysis in all family members. The mutation IVS1–2AT did not create a restriction site and was analyzed in all family members by bi-directional sequencing of the exon 2 PCR product. These two mutations were further tested in 70 healthy Caucasian individuals using the appropriate screening methods.
DNA sequencing
Sequencing was carried out with the DyeDeoxy Terminator Cycle Sequencing Ready Reaction kit [Applied Biosystems (ABI), Warrington, UK], performed according to the ABI standard protocol with 100 ng of exonuclease I and shrimp alkaline phosphatase-treated PCR products, with the same primers that were used for PCR amplification, and the ABI 377 automated DNA sequencer.
RT–PCR analysis
Total RNA was purified from adult lymphocytes, retina and cultured skin fibroblasts by the guanidium isothiocyanate method (39). Fetal brain RNA was purchased from Research Genetics (Huntsville, AL), and adult liver total RNA from Clontech (Palo Alto, CA). RT–PCR was performed with total RNA (500 ng) from each tissue with 20 U of Expand Reverse Transcriptase (Boehringer Mannheim, Mannheim, Germany). The primer 31R (5'-tgtcgtaaacaggagtccct-3', within exon 31 of the COL18A1 gene) was used for reverse transcription. The primers 2F (5'-ctgacggtcctggggagag-3'; exon 2 of COL18A1) and 4R (5'-gccagcccgacgtcgggg-3'; exon 4 of COL18A1) were used to amplify 220 bp of the short isoform of the COL18A1 cDNA; this PCR reaction was performed with Platinum Pfx DNA Polymerase (Gibco BRL), according to the manufacturer’s protocol. The primers 3F (5'-gggcgcccacacaaccga-3'; exon 3 of COL18A1) and 4R were used to amplify 207 bp of the long isoform of the cDNA. Each amplified product was confirmed by bi-directional sequencing. Cycling conditions for the sequencing of the PCR product from primers 2F/4R (a CG-rich region) were: 97°C for 2 min; 35 cycles at 97°C for 20 s, 50°C for 20 s and 55°C for 3 min. ß-actin was used as a positive control for all the RT–PCR reactions. PCR products were visualized in 8% acrylamide gel (acrylamide:N,N'-methylenebisacrylamide, 29:1) stained with ethidium bromide.
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ACKNOWLEDGEMENTS |
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The authors are very grateful to Dr Sallun for retina tissue, Luciana Vasques for mRNA from skin fibroblast cell lines, and Dr Roger Reeves, Dr Jeffrey Murray, Dr Lap-Tsui and Dr Roderick McInnes for valuable suggestions. We are also indebted to Eloísa de Sá Moreira, Dinamar Gaspar, Dr Isaac Neustein, Dr Suely Marie, Dr Rita C. Pavanello, Constância Urbano, Elisângela P.S. Quedas, Marta Canovas and Antônia M.P. Cerqueira for their constant help. This work was supported by grants from the FAPESP, PRONEX, CNPq. M.R.P.-B. is also supported in part by an international research scholars grant from the HHMI.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +55 11 3818 7563; Fax: +55 11 3818 7419; Email: passos@ib.usp.br
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