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Now showing items 1 - 16 of 27

  • Confirmation of the type 2 myotonic dystrophy (CCTG)(n) expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: A single shared haplotype indicates an ancestral founder effect RID A-9210-2012

    Bachinski, LL   Udd, B   Meola, G   Sansone, V   Bassez, G   Eymard, B   Thornton, CA   Moxley, RT   Harper, PS   Rogers, MT   Jurkat-Rott, K   Lehmann-Horn, F   Wieser, T   Gamez, J   Navarro, C   Bottani, A   Kohler, A   Shriver, MD   Sallinen, R   Wessman, M   Zhang, SX   Wright, FA   Krahe, R  

    Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be similar to200-540 generations.
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  • Proximal myotonic dystrophy mimicking progressive muscular atrophy

    Rotondo, G   Sansone, V   Cardani, R   Mancinelli, E   Krahe, R   Stangalini, D   Meola, G  

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  • Proximal myotonic dystrophy - A family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: Heterogeneity of proximal myotonic syndromes?

    Udd, B   Krahe, R   WallgrenPettersson, C   Falck, B   Kalimo, H  

    We describe a family with an autosomal dominant, multisystem disorder, consisting of late-onset proximal muscular dystrophy, electrophysiological myotonia, cataracts, late-onset deafness and male hypogonadism. Four patients were available for clinical examinations. Examination of asymptomatic family members revealed another patient with bilateral cataracts but without definite muscle disorder. Five deceased members of the family had proximal muscle weakness, reportedly or confirmed in medical records. Molecular examination of genomic DNA showed no expansion of the unstable (CTG)n trinucleotide repeat on chromosome 19q13.3 associated with myotonic dystrophy (DM). Linkage to two loci implicated in other myotonic disorders, the muscle chloride channel (CLCNI) gene, and the muscle sodium channel (SCN4A) gene, was assessed and excluded. The clinical findings differ from those described in proximal myotonic myopathy (PROMM), in terms of the more severe muscle involvement with atrophy of affected muscles and the hearing loss. These findings suggest phenotypic and probably genetic heterogeneity among the proximal myotonic syndromes. (C) 1997 Elsevier Science B.V.
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  • The gamma-tubulin gene family in humans

    Wise, DO   Krahe, R   Oakley, BR  

    Despite the central role of gamma-tubulin in the organization of the microtubule cytoskeleton, the gamma-tubulin gene family in humans has not been characterized. We now report the identification of a second expressed human gamma-tubulin gene (TUBG2) and a gamma-tubulin pseudogene (TUBG1P) in addition to the previously identified gamma-tubulin gene (TUBG1). Evidence from Southern hybridizations suggests that there are probably no additional gamma-tubulin sequences in the human genome. TUBG1 and TUBG2 are within 20 kb of each other in region q21 of chromosome 17, and TUBG1P is on chromosome 7. The proteins encoded by TUBG1 and TUBG2 share 97.3% amino acid identity, and the two genes are coexpressed in a variety of tissues. Previous studies of gamma-tubulin in human tissues and cell lines have been based on the tacit assumption that a single gamma-tubulin (the gamma-tubulin encoded by TUBG1) was present. While this assumption is not correct, the similarity of the products of TUBG1 and TUBG2 suggests that results of previous immunolocalization and immunoprecipitation studies in human cells and tissues are likely to be valid. In addition, any pharmacological agents that target one human gamma-tubulin are likely to target both. (C) 2000 Academic Press.
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  • Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1

    Virtaneva, K   DAmato, E   Miao, IM   Koskiniemi, M   Norio, R   Avanzini, G   Franceschetti, S   Michelucci, R   Tassinari, CA   Omer, S   Pennacchio, LA   Myers, RM   DieguezLucena, JL   Krahe, R   delaChapelle, A   Lehesjoki, AE  

    Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder that occurs with a low frequency in many populations but is more common in Finland and the Mediterranean region(1,2). It is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures with onset at age 6-15 years, typical electroencephalographic abnormalities and a variable rate of progression between and within families(3-5). Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval(7-9), positional cloning identified the gene encoding cystatin B (CST6), a cysteine protease inhibitor, as the gene underlying EPM1 (ref. 10). Levels of messenger RNA encoded by CST6 were dramatically decreased in patients. A 3' splice site and a stop codon mutation were identified in three families, leaving most mutations uncharacterized(10). In this study, we report a novel type of disease-causing mutation, an unstable 15- to 18-mer minisatellite repeat expansion in the putative promoter region of the CST6 gene. The mutation accounts for the majority of EPM1 patients worldwide. Haplotype data are compatible with a single ancestral founder mutation. The length of the repeat array differs between chromosomes and families, but changes in repeat number seem to be comparatively rare events.
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  • A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat.

    Boucher, C A   King, S K   Carey, N   Krahe, R   Winchester, C L   Rahman, S   Creavin, T   Meghji, P   Bailey, M E   Chartier, F L  

    Myotonic dystrophy (DM) is associated with a (CTG)n trinucleotide repeat expansion in the 3'-untranslated region of a protein kinase-encoding gene, DMPK, which maps to chromosome 19q13.3. Characterisation of the expression of this gene in patient tissues has thus far generated conflicting data on alterations in the steady state levels of DMPK mRNA, and on the final DMPK protein levels in the presence of the expansion. The DM region of chromosome 19 is gene rich, and it is possible that the repeat expansion may lead to dysfunction of a number of transcription units in the vicinity, perhaps as a consequence of chromatin disruption. We have searched for genes associated with a CpG island at the 3' end of DMPK. Sequencing of this region shows that the island extends over 3.5 kb and is interrupted by the (CTG)n repeat. Comparison of genomic sequences downstream (centromeric) of the repeat in human and mouse identified regions of significant homology. These correspond to exons of a gene predicted to encode a homeodomain protein. RT-PCR analysis shows that this gene, which we have called DM locus-associated homeodomain protein (DMAHP), is expressed in a number of human tissues, including skeletal muscle, heart and brain.
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  • N-(4-hydroxyphenyl)retinamide and nitric oxide pro-drugs exhibit apoptotic and anti-invasive effects against bone metastatic breast cancer cells RID A-7040-2008

    Simeone, AM   Colella, S   Krahe, R   Johnson, MM   Mora, E   Tari, AM  

    Breast cancer most frequently metastasizes to bone causing decreased quality of life and morbidity. Since current treatments are palliative, strategies to prevent bone metastases in breast cancer patients are required. There is substantial evidence indicating that high levels of nitric oxide (NO) suppress tumor growth and metastasis in vivo. We hypothesize that agents that produce high concentrations of NO could prevent the spread of breast cancer to bone. We previously demonstrated that the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) produces high levels of NO via the induction of NO synthases. NO pro-drugs are designed to produce large amounts of NO without inducing NO synthases but upon metabolism by their intracellular targets. The objective of this study was to determine the effectiveness of 4-HPR and an NO pro-drug, diethylamineNONOate/AM (NONO-AM), in inhibiting the growth and invasiveness of bone metastatic breast cancer cells. Parental MDA-MB-231 breast cancer cells were resistant to 4-HPR-induced apoptosis at clinically relevant doses, whereas 4-HPR-induced apoptosis in a dose-dependent manner in MDA-MB-231/F10 bone metastatic breast cancer cells. Unlike 4-HPR, NONO-AM induced apoptosis in a dose-dependent manner in both parental MDA-MB-231 cells and F10 cells. The bone metastatic F10 cells were more sensitive to the anti-invasive effects of 4-HPR and NONO-AM than were MDA-MB-231 cells. Although suppression of matrix metalloprotease-9 activity may be one mechanism by which 4-HPR decreases the invasion of F10 cells, it does not appear to be the anti-invasion mechanism of NONO-AM. These in vitro results suggest that 4-HPR and NO pro-drugs may be effective chemopreventive agents against bone metastatic breast cancer.
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  • Gene amplification in PNETs/medulloblastomas: mapping of a novel amplified gene within the MYCN amplicon

    Fruhwald, MC   O'Dorisio, MS   Rush, LJ   Reiter, JL   Smiraglia, DJ   Wenger, G   Costello, JF   White, PS   Krahe, R   Brodeur, GM   Plass, C  

    Objectives-The pathological entity of primitive neuroectodermal tumour/medulloblastoma (PNET/MB) comprises a very heterogeneous group of neoplasms on a clinical as well as on a molecular level. We evaluated the importance of DNA amplification in medulloblastomas and other primitive neuroectodermal tumours (PNETs) of the CNS. Method-Restriction landmark genomic scanning (RLGS), a method that allows the detection of low level amplification, was used. RLGS provides direct access to DNA sequences circumventing positional cloning efforts. Furthermore, we analysed several samples by CGH. Design-Twenty primary medulloblastomas, five supratentorial PNETs, and five medulloblastoma cell lines were studied. Results-Although our analysis confirms that gene amplification is generally a rare event in childhood PNET/MB, we found a total of 17 DNA fragments that were amplified in seven different tumours. Cloning and sequencing of several of these fragments confirmed the previous finding of MYC amplification in the cell line D341 Med and identified novel DNA sequences amplified in PNET/MB. We describe for the first time amplification of the novel gene, NAG, in a subset of PNET/MB. Despite genomic amplification, NAG was not overexpressed in the tumours studied. We have determined that NAG maps less than 50 kb 5' of DDX1 and approximately 400 kb telomeric of MYCN on chromosome 2p24. Conclusion-We found a similar but slightly higher frequency of amplification than previously reported. We present several DNA fragments that may belong to the CpG islands of novel genes amplified in a small subset of PNET/MB. As an example we describe for the first time the amplification of NAG in the MYCN amplicon in PNET/MB.
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  • Genome-wide loss of heterozygosity analysis of WTI-wild-type and WTI-mutant Wilms tumors RID A-7040-2008

    Ruteshouser, EC   Hendrickson, BW   Colella, S   Krahe, R   Pinto, L   Huff, V  

    Wilms tumor (WT) is genetically heterogeneous, and the one known WT gene, WTI at 11p13, is altered in only a subset of WTs. Previous loss of heterozygosity (LOH) analyses have revealed the existence of additional putative WT genes at 11p15, 16q, and 1p, but these analyses examined only one or a handful of chromosomes or looked at LOH at only a few markers per chromosome. We conducted a genome-wide scan for LOH in WT by using 420 markers spaced at an average of 10 cM throughout the genome and analyzed the data for two genetically defined subsets of WTs: those with mutations in WT1 and those with no detectable WT1 alteration. Our findings indicated that the incidence of LOH throughout the genome was significantly lower in our group of WTs with WT1 mutations. In WT1-wild-type tumors, we observed the expected LOH at 11p, 16q, and 1p, and, in addition, we localized a previously unobserved region of LOH at 9q. Using additional 9q markers within this region of interest, we sublocalized the region of 9q LOH to the 12.2 Mb between D9S283 and a simple tandem repeat in BAC RIP11- 17718, a region containing several potential tumor-suppressor genes. As a result, we have established for the first time that WT/-mutant and WT1-wild-type WTs differ significantly in their patterns of LOH throughout the genome, suggesting that the genomic regions showing LOH in WTI-wild-type tumors harbor genes whose expression is regulated by the pleiotropic effects of WTI. Our results implicate 9q22.2-q31.1 as a region containing such a gene. (c) 2005 Wiley-Liss, Inc.
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  • Identification of a testis-expressed creatine transporter gene at 16p11.2 and confirmation of the X-linked locus to Xq28.

    Iyer, G S   Krahe, R   Goodwin, L A   Doggett, N A   Siciliano, M J   Funanage, V L   Proujansky, R  

    Creatine and creatine phosphate act as a buffer system for the regeneration of ATP in tissues with fluctuating energy demands. Following reports of the cloning of a creatine transporter in rat, rabbit, and human, we cloned and sequenced a creatine transporter from a human intestinal cDNA library. PCR amplification of genomic DNAs from somatic cell hybrid panels localized two creatine transporter (CT) genes: CT1 to Xq26-q28 and CT2 to 16p11.2. Refinement of CT1 to Xq28 was confirmed by FISH. Identification of CT2 sequences in YACs and cosmid contigs that had been ordered on human chromosome 16 enabled its assignment to the proximal end of 16p11.2. Sequencing of the CT2 gene identified sequence differences between CT1 and CT2 transcripts that were utilized to determine that CT2 is expressed in testis only. CT2 is the most proximally identified gene on chromosome 16p to date. The existence of an autosomal, testis-specific form of the human creatine transporter gene suggests that creatine transporter activity is critical for normal function of spermatazoa following meiosis.
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  • Directional hearing is only weakly dependent on the rise time of acoustic stimuli

    Krahe, R   Larsen, ON   Ronacher, B  

    First-spike latency differences between left and right auditory-nerve fibers have been proposed as one of the physiological cues for sound localization. Since first-spike latency depends not only on stimulus intensity, but also on the steepness of the amplitude rise of a sound stimulus, differences in first-spike latency are not a simple function of interaural level differences but also a function of stimulus rise time. We therefore investigated whether rise time influences human directional hearing in a localization paradigm. Subjects tended to localize a 3-kHz tone pulse with a long (18-ms) rise time further to the side than one with a short (2-ms) rise time delivered from the same source. The small size of this effect and its large inter-individual variability, however, suggest that it is of minor importance for human directional hearing, (C) 2000 Acoustical Society of America. [S0001-4966(00)01902-0].
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  • Ranking of CT in diagnosis of fistulae

    Jung, G   Krahe, R   Brochhagen, HG   Kruger, K   Lackner, K  

    Purpose: The purpose of the study was to determine the value of computed tomagraphy (CT) in demonstrating fistulae in comparison with conventional radiographic methods. Methods: In a prospective study 25 patients were evaluated by conventional radiographic methods and CT. Results: The identification of the fistulous tract was possible with CT in 27 of 29 cases, whereas 2 fistulae could only be detected by indirect signs. Furthermore, CT showed a larger extent of the fistulous tract in 5 patients and revealed complications such as inflammatory mass, abscess or ostsomyelitis in 11 cases. Conclusion: CT seems to be superior in demonstrating the extent of a fistulous tract and provides valuable information on the surrounding structures.
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  • Aberrant hypermethylation of the major breakpoint cluster region in 17p11.2 in medulloblastomas but not supratentorial PNETs

    Fruhwald, MC   O'Dorisio, MS   Dai, ZY   Rush, LJ   Krahe, R   Smiraglia, DJ   Pietsch, T   Elsea, SH   Plass, C  

    Deletions of 17p have been consistently reported in up to 50% of medulloblastomas (MBs), and the major breakpoint interval has been localized to chromosome segment 17011.2. Based on several reports linking aberrant DNA methylation and chromosomal disruption, we examined the methylation pattern in this region by employing restriction landmark genomic scanning (RLGS), Several CpG islands located in the major breakpoint cluster region were identified using a bacterial artificial chromosome (BAC) contig of the breakpoint region. A long-range methylation map was established for 20 MBs and 5 supratentorial primitive neuroectodermal tumors (stPNETs). Selected CpG islands were examined using Southern and bisulfite sequencing analysis. Aberrantly hypermethylated CpG islands in 17p11.2 were found in 33% of MBs. Interestingly, one CpG island was methylated in MBs, but not in any of the examined stPNETs. A BAC clone covering three of the methylated CpG islands was partially sequenced in the search for a potential tumor suppressor gene. None of the expressed sequence tag sequences and full-length mouse/human cDNAs that were associated with aberrant methylation showed a change in expression levels due to methylation. The potential link between chromosomal instability in 17p11.2 and hypermethylation in this region is discussed. (C) 2001 Wiley-Liss, Inc.
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  • Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families RID A-9179-2008

    Barkardottir, RB   Sarantaus, L   Arason, A   Vehmanen, P   Bendahl, PO   Kainu, T   Syrjakoski, K   Krahe, R   Huusko, P   Pyrhonen, S   Holli, K   Kallioniemi, OP   Egilsson, V   Kere, J   Nevanlinna, H  

    The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct similar to 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.
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  • Report of the 115th ENMC workshop: DM2/PROMM and other myotonic dystrophies. 3rd Workshop, 14-16 February 2003, Naarden, The Netherlands.

    Udd, B   Meola, G   Krahe, R   Thornton, C   Ranum, L   Day, J   Bassez, G   Ricker, K  

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  • Pooled analysis of loss of heterozygosity in breast cancer: a genome scan provides comparative evidence for multiple tumor suppressors and identifies novel candidate regions

    Miller, BJ   Wang, D   Krahe, R   Wright, FA  

    Somatic loss of heterozygosity (LOH) has been widely reported in breast cancer as a means of identifying putative tumor-suppressor genes. However, individual studies have rarely spanned more than a single chromosome, and the varying criteria used to declare LOH complicate efforts to formally differentiate regions of consistent versus sporadic (random) loss. We report here the compilation of an extensive database from 151 published LOH studies of breast cancer, with summary data from 115,000 tumors and primary allelotypes from 14,300 tumors. Allelic loss was evaluated at 1,168 marker loci, with large variation in the density of informative observations across the genome. Using studies in which primary allelotype information was available, we employed a likelihood-based approach with a formal chromosomal instability and selection model. The approach seeks direct evidence for preferential loss at each locus compared with nearby loci, accounts for heterogeneity across studies, and enables the direct comparison of candidate regions across the genome. Striking preferential loss was observed (in descending order of significance) in specific regions of chromosomes 7q, 16q, 13q, 17p, 8p, 21q, 3p, 18q, 2q, and 19p, as well as other regions, in many cases coinciding with previously identified candidate genes or known fragile sites. Many of these observations were not possible from any single LOH study, and our results suggest that many previously reported LOH results are not systematic or reproducible. Our approach provides a comparative framework for further investigation of regions exhibiting LOH and identifies broad genomic regions for which there exist few data.
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