Human Molecular Genetics, 2001, Vol. 10, No. 13 1359-1368
© 2001 Oxford University Press
OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance
1Molekulargenetisches Labor der Universitäts-Augenklinik, Auf der Morgenstelle 15, D-72076 Tübingen, Germany, 2Universitäts-Augenklinik, Tübingen, Germany, 3Universitäts-Augenklinik, Essen, Germany, 4Augenklinik, Universitäts-Klinikum Benjamin Franklin, Berlin, Germany and 5Institute of Ophthalmology, Department of Molecular Genetics, University College London, London, UK
Received February 14, 2001; Revised and Accepted April 11, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein cause autosomal dominant optic atrophy (ADOA) linked to chromosome 3q28–q29. Here we report screening of the OPA1 gene in a sample of 78 independent ADOA families. OPA1 mutations were identified in 25 patients (detection rate 32.1%) including 16 novel mutations. We successfully amplified OPA1 cDNA prepared from leukocyte RNA of three patients, and found the amount of transcripts harboring the Arg366Stop mutation was significantly reduced compared with transcripts derived from the normal chromosome. Analysis of the distribution of OPA1 mutations in ADOA revealed that most missense mutations cluster within the putative GTPase domain, and that there is a preponderance of mutations, which result in premature translation termination. These observations support the notion that haploinsufficiency may represent a major pathomechanism for ADOA. In addition, we identified an ADOA patient who is a compound heterozygote for two OPA1 missense mutations. The fact that this patient is by far more severely affected than her simple heterozygotic parents and siblings implies that at least these OPA1 alleles behave semi-dominantly rather than purely dominantly. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Autosomal dominant optic atrophy (ADOA) is the most frequent form of hereditary optic neuropathies with an estimated disease prevalence ranging between 1:12 000 (1,2) and 1:50 000 (3) in different populations. ADOA is a progressive disorder with onset in the first decade of life, and clinically characterized by a loss of visual acuity, development of central, paracentral or coecocentral scotomas, bilateral atrophy of the optic nerve and color vision disturbances (4–6). ADOA exhibits variable expression even within families, and in some families asymptomatic carriers have been observed (4,7,8). Histological post-mortem examination of affected donor eyes suggests that the fundamental pathology results from a degeneration of the retinal ganglion cells followed by ascending atrophy of optic nerve fibers (9,10). A first locus for ADOA (OPA1, OMIM 165500) was mapped to chromosome 3q28–q29 in Danish families (11). This locus was subsequently confirmed and refined by studies in British, American, Cuban and French families (12–16). However, ADOA is genetically heterogeneous and a second locus (OPA4) linked to markers on chromosome 18q12.2–q12.3 has been described in an American family of German descent (17).
Refined genetic mapping placed the OPA1 gene within a 1–2 cM interval flanked by the marker loci D3S3669 and D3S3562 (18). Applying a positional cloning approach, yeast artificial chromosome and P1-derived artificial chromosome contigs were established and used to localize the expressed sequence tag SHGC37414, adopted from a brain cDNA of unknown function (KIAA0567), within the disease critical region (19). Subsequently, we and others were able to demonstrate that mutations in this gene, now designated the OPA1 gene, cause ADOA linked to chromosome 3q28–q29 (20,21). The OPA1 gene consists of 28 coding exons covering a genomic region >60 kb. The gene is widely expressed, but most abundant in the retina. The OPA1 gene encodes a 960 amino acid polypeptide with similarities to specific GTP-binding proteins of the dynamin protein family (20). The presence of typical sequence features (i.e. basic leader, MPP and MIP cleavage sites) at the N-terminus suggests that the OPA1 polypeptide is imported into the mitochondrion, and may represent the human ortholog of the Saccharomyces cerevisiae MgmI and the Schizosaccharomyces pombe MspI proteins, which are important for mitochondrial inheritance and maintenance in these organisms (22,23).
In this report, we addressed the spectrum and distribution of OPA1 mutations in a panel of 78 unrelated ADOA index patients, and the detectability of OPA1 mutations in leukocyte cDNA. The identification of a considerable number of novel OPA1 mutations enabled us to establish a first profound mutation spectrum of the OPA1 gene which provides new insights into the disease mechanism of ADOA. Furthermore, we describe an example of a severely affected patient with two compound heterozygous OPA1 mutations, which provides first evidence for a semi-dominant inheritance of ADOA.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Identification of OPA1 mutations in ADOA patients
We screened 78 independent cases with a clinical diagnosis of ADOA for the presence of mutations in the OPA1 gene. All 28 coding exons were analyzed by either complete direct sequencing of genomic PCR fragments (20 index patients) or combined single-strand conformation polymorphism (SSCP)/heteroduplex analysis followed by direct sequencing of samples showing apparent band shifts (58 unrelated patients).
In total, we identified OPA1 mutations in 25 out of the 78 ADOA patients (detection rate 32.1%). Four of these cases have been described previously (20). Among the remaining patients, we identified 18 different mutations including seven missense mutations (808G
A/Glu270Lys, 818AC/Asp273Ala, 868CT/Arg290Trp, 869GT/Arg290Gln, 1313AT/Asp438Val, 1402AG/Lys468Glu, 2354AG/Gln785Arg), two stop codon mutations (6GA/Trp2Stop and 629CA/Ser210Stop), one in-frame deletion (1651–1653delTGC/Cys551del), five frameshift (fs) mutations (932delC/Ala311fs, 1072–1093del/Ala358fs, 1152–1153delAA/Leu384fs, 2125–2138del-insGGATCGACACAC/Ile709fs, 2708–2711delTTAG/Val903fs) and three putative splice site mutations (1065+3AC, 2611+1GC and 2707+2TC) (Table 1). Of these mutations, only two, the Arg290Gln missense mutation found in family OAK51 and the 2708–2711delTTAG deletion detected in families OAK52 and OAK54, have already been found in other ADOA families (20,21). Additional novel recurrent mutations include one stop codon mutation, Trp2Stop, in families OAK55 and OAK87, and two missense mutations, Asp438Val in families OAK27 and OAK28 and Lys468Glu in families OAK8 and OAK16.
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Cosegregation analysis by PCR/restriction fragment length polymorphism (RFLP) analysis or SSCP analysis was performed in families with several affected members, for which samples were available (12 families). In these families, all affected members consistently carried the mutant allele. Furthermore, we excluded all mutations in a panel of 100 healthy controls (n = 200 chromosomes).
In addition, we identified a number of polymorphisms within the coding and flanking intron and untranslated region (UTR) sequences of the OPA1 gene (Table 2).
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Detection of mutations in leukocyte RNA
The OPA1 gene is widely expressed in various tissues albeit at varying abundances (20). We therefore addressed the question of whether the OPA1 gene is also expressed in blood leukocytes, which might allow simplification of mutation detection by analyzing OPA1 cDNA. We isolated total leukocyte RNA from three ADOA patients, one carrying the 1313A
T/Asp438Val missense mutation, one with the 1096CT/Arg366Stop nonsense mutation and, finally, one patient with the 1065+3AC putative splice site mutation. Single-stranded cDNA was synthesized by reverse transcription and used to amplify overlapping cDNA fragments for subsequent direct DNA sequencing. Comparative inspection of genomic and cDNA sequence profiles revealed that the relative amount of transcripts from the missense allele is only slightly reduced while the transcripts derived from the nonsense mutation allele are considerably under-represented in leukocytes (Fig. 1A). Semi-quantitative RT–PCR/RFLP analysis further confirmed the reduced expression of the Arg366Stop allele (Fig. 1B). Sequencing of the OPA1 cDNA prepared from the patient with the 1065+3AC substitution revealed that this alteration induces the skipping of the preceding exon 10 in mature transcripts (data not shown).
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Two mutant OPA1 alleles are present in a severely affected ADOA patient
Two heterozygous missense mutations, 808G
A/Glu270Lys and 868CT/Arg290Trp, both located in exon 8 of the OPA1 gene, were identified in the index patient of family OAK86. Segregation analysis within the family revealed that the patient is compound heterozygous for these mutations since she inherited the Glu270Lys mutation from her father and the Arg290Trp mutation from her mother. Her siblings are simple heterozygotes for either one of the two mutations (Fig. 2). Clinical examination showed that the compound heterozygous index patient is the most severely affected family member. She presented with visual acuities of 0.2 and central scotomas on both eyes at 30 years of age. Pattern VEP showed prolonged latencies, and color vision testing revealed a slight dyschromatopsia (imperfect color discrimination) with no clear-cut axis of confusion. Fundus examination revealed total pallor of optic discs on both eyes. In contrast, both parents and the siblings presented with a much milder disease manifestation; visual acuities were normal or only slightly reduced. Visual fields were normal, as well as color vision. Pattern VEPs were mostly in the normal range or showed only slightly prolonged latencies. However, we consistently observed pallor of the optic discs which was taken as a main evidence for the presence of a pathological condition affecting the optic nerve. We thus suggest that both missense mutations observed in this pedigree represent, per se, mild disease alleles, with an additive effect if encountered in a single subject.
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Types and distribution of OPA1 mutations
The delineation of disease-causing mutations for a given gene provides a valuable data source for the identification of domains critical for the protein’s proper function. This strategy is particularly useful for novel proteins, such as OPA1, on whose function one can only speculate.
Combining our data with those of the two initial reports (20,21), 27 different OPA1 mutations in 35 ADOA families have been identified so far (Table 1; Fig. 3). Frameshift-causing insertions and deletions account for the majority of the different mutations (10/27), followed by missense mutations (8/27), splice site mutations (4/27), stop mutations (3/27) and in-frame deletions (2/27). Thus, the spectrum of OPA1 mutations points out a clear preponderance of mutations which result in truncated OPA1 polypeptides. There is a considerable diversity of OPA1 mutations, which contrasts the proposed strong founder effects in British and Danish ADOA patients based on haplotype comparisons (24,25). Only the 2708–2711delTTAG mutation, which has been previously observed in three families originating from France and Belgium (21) and two further German families in this study, displays a notably increased frequency.
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The mutations are not evenly distributed along the length of the OPA1 polypeptide. There is a significant clustering of more than half of all different mutations between residues 270 and 468 (Fig. 3). Interestingly, this segment, which corresponds to the putative GTPase domain of the OPA1 protein, includes all but one of the identified missense mutations. The GTPase domain represents the most conserved part of the OPA1 protein when compared with other members of the dynamin protein family. This domain includes the typical tripartite GTP-binding motif needed for phosphate binding (GXXXXGKS/T), coordination of Mg2+ (DXXG) and nucleotide binding (T/NKXD) (22,26), and the dynamin sequence signature (27). A minor cluster of mutations, including two frameshift and two splice site mutations, is located in close vicinity to the C-terminus of the polypeptide. This suggests that the C-terminal sequence is essential for effective expression and/or stability of the OPA1 transcript, or contains important elements for the structural or functional integrity of the polypeptide.
Phenotypes of ADOA patients with OPA1 mutations
Table 3 summarizes the clinical findings of index ADOA patients with OPA1 mutations. In most patients, disease onset was within the first decade of life. However, two patients, OAK51 and OAK28, reported much later onset of visual complaints. All index patients examined consistently showed pallor of the optic disc, which was mostly confined to the temporal half. Visual acuities varied from 0.05 to 0.8 but were similar for both eyes. Central and/or coecocentral scotomas were the visual field defects most commonly detected. One patient (OAK26) presented with peripheral constriction of the visual field combined with bilateral central scotoma. Color vision (tested with the saturated and the desaturated Panel D 15 test) ranged from normal to severe dyschromatopsia (imperfect color discrimination) without clear-cut axis of confusion. Only a few patients presented with classical tritanopia (lack of short-wavelength sensitivity). Severity of symptoms correlated with neither the type nor the site of the mutation, nor the patient’s age. Even patients carrying the same mutation showed highly variable disease expression (i.e. Val903fs mutation in OAK52 and OAK54). Whereas both index patients with the Trp2Stop mutation present with rather good visual acuities (0.7–0.8) and tritanopia, clinical examination of the affected father of subject OAK55/EK revealed a visual acuity of 0.5/0.4, similar to other ADOA cases.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein are responsible for ADOA linked to chromosome 3q28–q29 (20,21). In this study, we address the prevalence of OPA1 mutations in clinically defined ADOA cases, the spectrum of mutations and their distribution along the OPA1 protein, and the expression of mutant transcripts in leukocytes.
Among the 78 independent ADOA patients, we detected mutations in 25 cases, giving an overall detection rate of 32.1% of OPA1 mutations in clinical ADOA patients. This rate did not differ significantly between the sub-sets of patients screened by complete DNA sequencing (20 index patients) or SSCP/heteroduplex analysis (58 index patients), indicating sensitive performance of our SSCP/heteroduplex protocol.
Patients and families analyzed in this study were collected mainly on the basis of clinical diagnosis and included cases in which autosomal dominant inheritance could not be unequivocally established. Of the 25 index patients with OPA1 mutations, 21 belonged to the group of cases with evidence for dominant inheritance [21/50 (42%) detection rate], three patients were simplex cases [3/16 (18.75%) detection rate] and one patient belonged to a family with affected individuals in only one generation [1/3 (33.33%) detection rate]. This observation indicates that OPA1 mutations are predominantly present in multi-generation families, and it illustrates the suspicious genetic nature of the disease in sporadic cases and families with affected siblings only. These may represent examples of recessively X-linked or mitochondrially inherited disorders, clinically similar to ADOA [i.e. Leber’s hereditary optic neuropathy (LHON).] The actual prevalence of OPA1 mutations might be even higher if we take into consideration possible mutations in the, as yet undefined, promoter region of the OPA1 gene, and larger deletions, which remain undetectable by PCR-based screening approaches. On the other hand, it is reasonable to suggest that non-allelic genetic heterogeneity contributes to the large fraction of ADOA patients lacking OPA1 mutations in our screen. Recently, a second locus for ADOA has been mapped to chromosome 18q12 (17). The fact that this linkage study was performed on a family of German descent implies that some of our mostly German ADOA families might also be linked to this locus.
The sensitivity and practicability of OPA1 screening could perhaps be improved by cDNA analysis. We were able to show that OPA1 cDNA can be reliably amplified from leukocyte RNA and that putative splicing defects can be confirmed by this approach. We found that in leukocytes the 1313AT/Asp438Val allele and particularly the 1096CT/Arg366Stop allele are expressed at reduced levels in comparison to the wild-type allele (Fig. 1).
Studies in other genetic disorders and yeast have shown that transcripts containing premature stop codons are frequently subject to degradation (28). It has been observed that if the position of the premature termination is located >50 bp proximal to the final exon/intron junction, the mutant mRNA will fall to degradation. More distally terminated transcripts are usually stable (29,30). Whereas such a nonsense decay mechanism holds true at least for the nonsense mutation for OPA1 leukocyte transcripts, we did not observe selective skipping of the exon containing the stop mutation as described by Dietz and Kendzior Jr (31). Although cDNA-based screening is an attractive alternative to conventional exon-by-exon procedures, further studies will be necessary to determine its actual sensitivity for the screening of the OPA1 gene in ADOA.
Nonsense mutations including stop codon, frameshift and splice site mutations represent the majority of all OPA1 mutations involved in ADOA. At least some of them obviously represent functional null mutations since they produce severely truncated polypeptides, lacking the putative GTPase domain and the dynamin-related core region. The Trp2Stop mutation, for instance, results in an instant termination of translation and, thus, practically does not produce any product. Moreover, our analysis on leukocyte cDNA shows that the level of transcripts harboring nonsense mutations is considerably reduced at least in these cells. These observations suggest that haploinsufficiency for OPA1 might be a mechanism in ADOA. A single functional allele might be insufficient to maintain the maximum level of OPA1 transcripts observed in the retina, and thus explains why the clinical phenotype is restricted to the visual system although the gene is widely expressed (20). Preliminary data from in situ hybridization experiments indicate that within the retina OPA1 is predominantly expressed in the ganglion cell layer—an observation that is consistent with the suggested cellular pathology in ADOA (unpublished data). Although the function of the OPA1 polypeptide is not known, the presence of a typical leader sequence and the cellular co-localization of tagged OPA1 proteins with mitochondrial markers strongly support that the OPA1 polypeptide is imported into mitochondria (20,21). Interestingly, OPA1 shares significant homology with Mgm1 from S.cerevisiae and Msp1 from S.pombe, genes known to be important for mitochondrial inheritance and maintenance in these organisms (22,23). Using antibodies against the mitochondrial marker protein HSP60, Delettre et al. (21) observed disorganization of the mitochondrial network in monocytes of two ADOA patients with the OPA1 2708–2711delTTAG mutation. These observations suggest that ADOA caused by OPA1 mutations is a mitochondriopathy. This relationship is remarkably similar to LHON, which is caused by mutations in mtDNA-encoded genes for subunits of the complex I of the respiratory chain (32). It has been suggested that in this case the synergistic effect of mtDNA mutations and environmental factors eventually result in a decrease of oxidative phosphorylation (OXPHOS) capacity below a threshold that is critical for the functional integrity of retinal ganglion cells (33). However, this model does not explain why only certain mitochondrial defects result in optic atrophies and others do not. Further studies will be necessary to elucidate the higher susceptibility of retinal ganglion cells for these specific defects.
Most missense mutations cluster within or close to the putative GTPase domain and may reduce or prevent GTP-binding and/or GTP-hydrolysis. This suggests that GTPase activity is of particular importance for the functioning of the OPA1 protein. Whether such missense mutations represent functional null alleles compatible with the hypothesis of haploinsufficiency or rather induce a dominant-negative effect cannot be resolved at this stage. If the latter holds true, specific targets for such aberrant OPA1 proteins must exist in retinal ganglion cells. Remarkably, we did not observe any missense mutations at the N-terminus of the OPA1 protein, which is thought to represent the signal sequence for the import of the OPA1 protein into the mitochondrion (20,21). However, since these signal sequences are less conserved in primary sequence but rather an accumulation of basic residues followed by a weakly conserved cleavage site for mitochondrial import peptidases, amino acid substitutions may be more tolerable in the signal sequence than elsewhere in the OPA1 polypeptide sequence. Interestingly, we found two distinct OPA1 mutations segregating in one ADOA pedigree. While both affected parents and two of the affected children are simple heterozygotes for one or the other mutation, the third, most severely affected child is a compound heterozygote for both mutations. This, to our knowledge, is the first case of a patient carrying two mutant OPA1 alleles. Given an incidence of 1:12 000 to 1:50 000 for ADOA, this coincidence of mutant alleles represents a very rare situation. However, there are examples of preferential mating of subjects with the same condition due to social adherence. This case leads to two important conclusions: taking into account the severity of the clinical picture in the compound heterozygous patient, ADOA must be considered as a semi-dominant condition rather than a purely dominant disorder. The case also documents that the presence of two mutant OPA1 alleles is not lethal, per se, and even the clinical presentation can still be restricted to a loss of visual function. However, since both mutations cause only amino acid substitutions and, obviously, represent mild disease alleles, it may be hypothesized that these mutations merely disturb rather than completely inhibit OPA1 function.
ADOA patients with OPA1 mutations present with highly variable expression of visual symptoms. Visual acuities ranged between 0.04 and 0.8, and were mostly correlated with the presence of central or near central scotomas. Whereas pallor of optic discs was common in all patients, tritanopia was not a consistent clinical feature. In most patients, we rather noticed a general reduction in color matching capabilities without any clear axis of confusion.
Genotype–phenotype comparisons were mostly inconclusive. Neither the type of mutation (missense versus nonsense) nor the location of the mutation within the polypeptide follows a conclusive pattern. This may be explained by the variability in clinical expression between affected family members as reported in previous clinical studies and as also seen in this study between non-related patients carrying the same OPA1 mutation. Further studies in ADOA families and affected twins will be necessary to address the question of whether other genetic and/or epigenetic factors are responsible for the variability in clinical expression.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Patients and DNA samples
Patients were seen at various ophthalmological institutions, and the diagnosis of ADOA was based on ophthalmological examinations including visual acuity, visual field and color testing, fundoscopy and electrophysiology. In total, our sample comprises 78 independent cases with a clinical diagnosis of ADOA. Fifty patients were from pedigrees with affecteds in at least two subsequent generations, three were from families with multiple affected siblings and 16 patients were sporadic. For nine cases no family history was available. None of the families underwent prior marker analysis for linkage to the OPA1 locus on chromosome 3q28. Blood samples were taken from patients and family members after informed consent had been obtained. Genomic DNA was extracted from the blood samples according to standard procedures.
Genomic DNA amplification
Oligonucleotide primers (Table 4) for the amplification of all 28 coding exons were designed from flanking intron or UTR sequences using the Primer Picking Program available at the MIT/Whitehead Institute web site (http://www-genome.wi.mit.edu/). Standard 50 µl PCR reactions were carried out in 10 mM Tris–HCl pH 8.9, 50 mM KCl, 1.5–3 mM MgCl2 and 200 µM of each dNTP including 50–100 ng genomic DNA, 10 pmol of corresponding forward and reverse primers and 1 U AmpliTaq polymerase (Applied Biosystems, Weiterstadt, Germany). Typical cycling conditions were 94°C for 4 min, 35 cycles of 30 s at 94°C, 30 s at 53°C and 30 s at 72°C, and a final extension step of 7 min at 72°C.
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SSCP/heteroduplex analysis
For SSCP/heteroduplex analysis, PCR fragments were separated on 20 x 20 cm, 10% non-denaturing polyacrylamide gels either for 12 h at room temperature or for 17 h at 4°C for gels including 10% glycerol. Gels were silver-stained and samples showing band shifts for single- or double-strand products underwent direct DNA sequencing.
Mutation detection in leukocyte RNA
Leukocytes were isolated from total venous blood by Ficoll-Paque density centrifugation (Pharmacia Biotech, Freiburg, Germany) and total RNA was extracted with Trizol reagent (Life Technologies, Eggenstein, Germany). Oligo(dT)-primed total leukocyte RNA was reverse transcribed into single-stranded cDNA and used to amplify four overlapping cDNA segments (segments 1–4, PCR primers; Table 4) according to the manufacturer’s recommendations (RNA PCR Kit; Takara, Shiga, Japan). For semi-quantitative RFLP analysis of the 1096CT mutation, a 741 bp cDNA fragment was amplified with segment 2* primers (Table 4). RT–PCR products were purified, digested with TaqI and separated on a 1.8% agarose gel.
Sequencing
PCR and RT–PCR products were either purified by ultrafiltration (Centricon-100 cartridges; Amicon, Bedford, USA) or Qiaquick columns (Qiagen, Hilden, Germany). The samples were sequenced using Big Dye Terminator chemistry (Applied Biosystems, Weiterstadt, Germany) and separated on an ABI 377 DNA sequencer. The Lasergene Software package (DNASTAR, Lasergene Cooperation, London, UK) was used for editing and alignment of sequences.
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ACKNOWLEDGEMENTS |
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We thank all patients and family members for participation, H. Wilhelm, I. Moderau, C. Castellan and P. Bitoun for referring additional patients, S. Tippmann for providing service at the IZKF Tübingen core sequencing center, S. Schimpf for helpful assistance by RT–PCR analysis, and K. Pesch and S. Kohl for help on the manuscript. This work was supported by the DAAD (313/ARC) and a joint grant from the Bundesministerium für Bildung und Forschung and the Interdisziplinäres Zentrum für Klinische Forschung at the Medical Faculty Tübingen (01 KS 9602).
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +49 7071 2985032; Fax: +49 7071 295725; Email: wissinger@uni-tuebingen.de
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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