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T Gedde-Dahl

Publications and source records attributed to T Gedde-Dahl.

At least 19 recordsLinked to original sources
PubMed2005

Selecting and deselecting imatinib-resistant clones: observations made by longitudinal, quantitative monitoring of mutated BCR-ABL.

Resistance to imatinib during the treatment of chronic myeloid leukaemia (CML) is frequently associated with point mutations in the ABL gene encoding the ATP binding region likely to cause disease relapse. Early diagnosis and monitoring of these mutations may be important in order to prevent rapid expansion of resistant clones. We describe a quantitative mutation-specific PCR assay based on the readily available Taqman platform. Selectivity for the mutated target is conferred by mutation-specific primers destabilised by additional mismatches. The assay can be carried out in parallel to standard BCR-ABL quantification and is therefore more quickly compared to standard sequencing procedures. The sensitivity of the assay reaches 0.1%. It also allows for quantitative assessment of mutated clones. By analysing sequential samples of resistant subjects, we show how mutated clones were selected, maintained or deselected depending on the individual treatment setting. The high sensitivity and practical merits of this method makes it a good candidate for prospective molecular surveillance of patients at high risk for imatinib resistance.

Adult↗
PubMed2004

Activated prothrombin complex concentrate (FEIBA) treatment during surgery in patients with inhibitors to FVIII/IX.

Non-activated and activated prothrombin complex concentrates (PCC/aPCC) have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX (FVIII/IX) concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 14 minor and five major surgical and invasive diagnostic procedures in eight patients with congenital haemophilia A and inhibitors and in two patients with acquired haemophilia. When a loading dose of 100 U kg-1 of FEIBA was given followed by 200 U kg-1 day-1 in three divided doses every 8 h for 3 days, and then, when the daily dose was tapered to 100-150 U kg-1, no severe or unexpected bleeding complications were observed. However, one adverse event was observed. A 69-year-old man who suffered a myocardial infarction the third postoperative day following sigmoidectomy was managed safely with opiate analgesia, nitrates and diuretics, and the continued use of FEIBA(R).

Adult↗
PubMed2004

Life-long course and molecular characterization of the original Dutch family with epidermolysis bullosa simplex with muscular dystrophy due to a homozygous novel plectin point mutation.

Plectin is one of the largest and most versatile cytolinker proteins known. Cloned and sequenced in 1991, it was later shown to have nonsense mutations in recessive epidermolysis bullosa with muscular dystrophy. A dominant mutation in the gene was found to cause epidermolysis bullosa simplex Ogna without muscular dystrophy. Here we report the DNA sequencing of the plectin gene (PLEC1) in a Dutch family originally described in 1972 as having epidermolysis bullosa with muscular dystrophy. The results revealed homozygosity for a new plectin nonsense mutation at position 13187 and its specific 8q24 marker haplotype profile. Western blotting of cultured fibroblasts and immunofluorescence microscopy of skin biopsy confirm that the plectin protein expression is grossly reduced or absent. A summary of the life-long clinical course of the two affected brothers homozygous for the new E1914X mutation is given.

Base Sequence↗
PubMed2002

Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy.

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.

Adolescent↗
PubMed2001

[Genetic analysis in familial adenomatous polyposis].

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder caused by germline mutations in the APC gene. FAP is characterised by a variable, but normally large number of colorectal adenomas and variations in extracolonic manifestations. These variations are associated with specific mutations of the APC gene. MATERIAL AND METHODS: Representatives from 70 Norwegian families are under molecular investigation. Analyses have so far been concentrated on the part of the APC gene associated with classic FAP. RESULTS: Germline mutations causing FAP have been identified in 36 of the 70 families examined. All mutations identified are confined to the first half of the gene and correlate to classic FAP. INTERPRETATION: Because of the mutation heterogeneity in FAP, the size of the APC gene and variations in phenotype, it is a laborious task to identify the causative mutations. Better approaches to the analysis of the whole APC have now been established and will result in a higher degree of mutation detection independent of phenotype. Family history and phenotype-genotype correlations are still important guidelines for efficient molecular genetic analysis of the APC gene. Genetic surveillance, personal and socio-economic benefits from presymptomatic and predictive testing of members of FAP families are discussed.

Adenomatous Polyposis Coli↗
PubMed2001

Truncated typeXVII collagen expression in a patient with non-herlitz junctional epidermolysis bullosa caused by a homozygous splice-site mutation.

SUMMARY: Type XVII collagen (180-kDa bullous pemphigoid antigen) is a structural component of hemidesmosomes. Mutations in the type XVII collagen gene (COL17A1) have been established to be the molecular basis of non-Herlitz junctional epidermolysis bullosa (JEB-nH), an inherited skin blistering disorder. Here we report for the first time truncated type XVII collagen expression, caused by homozygosity for a COL17A1 donor splice-site mutation (4261+1 g --> c), which was identified by PCR amplification on genomic DNA. By RT-PCR and sequencing of cDNA derived from mRNA from the patient's cultured keratinocytes, we provide evidence of cryptic splicing and exon skipping, most abundantly of exon 52. JEB-nH patients with COL17A1 splice-site mutations resulting in an exon skip often have no immunologically detectable type XVII collagen. However, in our patient with the generalized atrophic benign epidermolysis bullosa subtype, a small amount of type XVII collagen was detectable in the skin, and immunoblotting of cultured keratinocytes revealed that the 180-kDa protein was 10 kDa shorter. We hypothesize that the function of this truncated type XVII collagen polypeptide, which is expressed at low levels, is impaired, explaining the JEB-nH phenotype.

Aged↗
PubMed2001

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Acanthosis Nigricans↗
PubMed2001

Generalized dystrophic epidermolysis bullosa: identification of a novel, homozygous glycine substitution, G2031S, in exon 73 of COL7A1 in monozygous triplets.

We report monozygous triplets affected with dystrophic epidermolysis bullosa (DEB). The female triplets were delivered by Caesarean section and skin fragility of each child, which was partly induced by trauma, was apparent from the third to fourth day of life. Clinically, the triplets were equally affected. Mutation analysis in this family revealed a novel recessively expressed glycine substitution, G2031S, in exon 73 of the collagen VII gene COL7A1. Most glycine substitutions in this gene region encoding for the triple helical domain of collagen VII are associated with milder, dominantly inherited phenotypes. By contrast, the novel point mutation of this study is clinically silent in the heterozygous state and leads to a severe DEB subtype when homozygous.

Collagen↗
PubMed2000

DXYS267: DYS393 and its X chromosome counterpart.

The GATA repeat DYS393 was reported in 1987 among other Y-specific short tandem repeats. It has since been used for forensic and evolutionary studies. We decided to test its Y-specificity when we found that female DNA gave amplicons, in agreement with recent GDB-recorded experiences on radiation hybrids. Parent-child triplets revealed that heterozygous daughters always carried the same paternally derived amplicon which, however, was not amplified in their fathers' DNAs. The X-assignment was verified in larger families. A half-new primer set with a new reverse DYS393 primer, outside the old one, resulted in X amplicons in females as well as Y and X amplicons in males. This new primer set defines the new DXYS267 (GDB Data Curation). DNA-sequencing revealed four base pair differences between the Y- and the X-sequences. Two are within the reverse primer site sequence, thus probably causing preferential hybridization to the Y sequence when using the conventional primers. The two others are within the repeat array, giving the regular repeat GATA in the Y-sequence, and TATA and GACA, respectively, in the X-sequence. Allele frequency distribution in DYS393 was studied in 300 unrelated Norwegian males, allele distribution in the X-locus in 48 Norwegian women. Even if allele repeat numbers are overlapping between the loci, leading to identical fragment lengths, the allele distribution is different between DYS393 and the X-chromosome locus. The differences between the two homologous loci on the Y and X indicate a considerable lap of time since common ancestry. To avoid co-amplification of the X-locus in DYS393 typing, primer A was elongated to include one of the sequence differences between the two loci. This to a considerable extent improved the specificity of the DYS393 primers.

Adenine↗
PubMed2000

Haplotype association and mutation analysis of the transglutaminase 1 gene for prenatal exclusion of lamellar ichthyosis.

Lamellar ichthyosis (LI) is an autosomal recessive keratinization disorder of the skin. Genetic heterogeneity has been shown for the disease and there is evidence for the involvement of the transglutaminase 1 (TGM1) gene on chromosome 14q11. We have previously identified chromosome 14q11 haplotypes associated with ichthyosis in the Norwegian population. In this paper we describe antenatal exclusion of ichthyosis in two Norwegian families by chromosome 14q11 haplotype association and direct mutation analysis. In one pregnancy, the 11-week old fetus at risk for LI was found to share only one disease-associated haplotype. A subsequent mutation analysis of the TGM1 gene in fetal DNA revealed that the fetus carried a novel 3795A-->T transversion. The affected proband was compound heterozygous for the mutations 3795A-->T and 3239G-->C resulting in an Asp430Val and a Val379Leu, respectively. In another LI family, the 11-week old fetus was found to be heterozygous for the 14q11 haplotype associated with the disease. Subsequent mutation analysis revealed that the fetus was heterozygous for the 2526A-->G transition in the splice site of intron 5 whereas the proband was homozygous for the same mutation. Our results show that haplotyping can be a useful tool for prenatal diagnosis in diseases with genetic heterogeneity.

Chromosomes, Human, Pair 14↗
PubMed1999

[Serotonin syndrome with fatal outcome caused by selective serotonin reuptake inhibitors].

The serotonin syndrome is a rare, but potentially fatal complication to treatment with serotonin reuptake inhibitors. Due to increasing prescription of these drugs the condition must be expected to occur more often. Symptoms include changes in mental status (confusion, agitation and restlessness), neuromuscular symptoms (shivering, ataxia, myoclonus and hyperreflexia) and autonomic dysfunction (fever, diaphoresis, hypertension and tachycardia). The syndrome is most often produced by concurrent use of two or more drugs that enhance serotonin neurotransmission. Monotherapy may also elicit the syndrome. We report the development of serotonin syndrome with a fatal outcome in a patient treated with paroxetin++. Interactions with alimemazin++, melperon++ and karbamazepin may have contributed to the outcome. The serotonin syndrome usually resolves within 24 hours when the suspected drugs are discontinued. However, there may be a dramatic progression of symptoms requiring intensive supportive care to prevent death.

Anticonvulsants↗
PubMed1997

Implications of intragenic marker homozygosity and haplotype sharing in a rare autosomal recessive disorder: the example of the collagen type XVII (COL17A1) locus in generalised atrophic benign epidermolysis bullosa.

Generalised atrophic benign epidermolysis bullosa (GABEB) is a form of junctional epidermolysis bullosa with a recessive mode of inheritance. The gene considered likely to be involved in this disease is COL17A1, since in the majority of GABEB patients the product of that gene, the 180-kD bullous pemphigoid antigen (BP180), is undetectable in skin. We have identified an intragenic COL17A1 microsatellite marker for which 83% of randomly selected control individuals are heterozygous. We observed homozygosity for different alleles of this marker in five out of six collagen type XVII-negative GABEB patients of different European descent. Five of the six COL17A1 alleles of three patients originating from the eastern part of the Netherlands were identical, as were the haplotypes including flanking markers. The 2342delG mutation was identified in all these five alleles. This confirms the expectation that due to genetic drift and hidden inbreeding for an autosomal recessive disorder with low gene frequency, such as collagen type XVII-negative GABEB, most disease alleles from a restricted geographical area will be "identical by descent". Our results demonstrate that involvement of a candidate gene can be confirmed by looking for identity by descent of highly informative intragenic markers.

Adult↗
PubMed1997

Modulation of disease severity of dystrophic epidermolysis bullosa by a splice site mutation in combination with a missense mutation in the COL7A1 gene.

Dystrophic epidermolysis bullosa (EBD) is a clinically heterogeneous skin disorder, characterized by abnormal anchoring fibrils (AF) and loss of dermal-epidermal adherence. EBD has been linked to the COL7A1 gene at chromosome 3p21 which encodes collagen VII, the major component of the AF. Here we investigated two unrelated EBD families with different clinical phenotypes and novel combinations of recessive and dominant COL7A1 mutations. Both families shared the same recessive heterozygous 14 bp deletion at the exon-intron 115 boundary of the COL7A1 gene. The deletion caused in-frame skipping of exon 115 and the elimination of 29 amino acid residues from the pro-alpha1(VII) polypeptide chain. As a result, procollagen VII was not converted to collagen VII and the C-terminal NC-2 propeptide which is normally removed from the procollagen VII prior to formation of the anchoring fibrils was retained in the skin. All affected individuals also carried missense mutations in exon 73 of COL7A1 which lead to different glycine-to-arginine substitutions in the triple-helical domain of collagen VII. Combination of the deletion mutation with a G2009R substitution resulted in a mild phenotype. In contrast, combination of the deletion with a G2043R substitution led to a severe phenotype. The G2043R substitution was a de novo mutation which alone caused a mild phenotype. Thus, different combinations of dominant and recessive COL7A1 mutations can modulate disease activity of EBD and alter the clinical presentation of the patients.

Adolescent↗
PubMed1997

Plectin abnormality in epidermolysis bullosa simplex Ogna: non-responsiveness of basal keratinocytes to some anti-rat plectin antibodies.

Epidermolysis bullosa (EB) is a heterogeneous group of genetic bullous skin diseases. The EB simplex group (EBS) is characterized by intraepidermal blistering. EBS-Ogna was first described as a separate entity based on clinical studies. Later genetic linkage of EBS-Ogna to the GPT locus for glutamate pyruvate transaminase (alanine transaminase) was detected and GPT was assigned to chromosome 8, then to the terminal long arm band 8q24. Plectin is an abundant and widespread cytoskeletal protein which has been proposed as a general crosslinking element of intermediate filaments. Human plectin has recently been cloned and in situ hybridized to chromosome 8q24. To examine whether plectin could be associated with EBS-Ogna we performed an immunohistochemical study with a panel of mAbs to rat plectin. Interestingly, 2 of these mAbs showed strong intracellular staining of the suprabasal and basal layer of the epidermis in all control samples, whereas no reactivity of the basal layer was found in the Ogna group. These results strongly suggest that plectin is involved in the pathogenesis of EBS-Ogna.

Animals↗
PubMed1996

The genetic basis of epidermolysis bullosa simplex with mottled pigmentation.

Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant skin diseases characterized by blistering, due to mechanical stress-induced degeneration of basal epidermal cells. It is now well-established that the three major subtypes of EBS are genetic disorders of the basal epidermal keratins, keratin 5 (K5) and keratin 14 (K14). Here we show that a rare subtype, referred to as EBS with mottled pigmentation (MP), is also a disorder of these keratins. Affected members of two seemingly unrelated families with EBS-MP had a C to T point mutation in the second base position of codon 24 of one of two K5 alleles, leading to a Pro: Leu mutation. This mutation was not present in unaffected members nor in 100 alleles from normal individuals. Linkage analyses mapped the defect to this type II keratin gene (peak logarithm of odds score at phi = 0 of 3.9), which is located on chromosome 12q11-q13. This provides strong evidence that this mutation is responsible for the EBS-MP phenotype. Only conserved between K5 and K6, and not among any of the other type II keratins, Pro-24 is in the nonhelical head domain of K5, and only mildly perturbs the length of 10-nm keratin filaments assembled in vitro. However, this part of the K5 head domain is likely to protrude on the filament surface, perhaps leading to additional aberrations in intermediate filament architecture and/or in melanosome distribution that are seen ultrastructurally in patients with the mutation.

Alleles↗
PubMed1996

Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study.

In a pilot I/II study we have tested synthetic ras peptides used as a cancer vaccine in 5 patients with advanced pancreatic carcinoma. The treatment principle used was based on loading professional antigen-presenting cells (APCs) from peripheral blood with a synthetic ras peptide corresponding to the ras mutation found in tumour tissue from the patient. Peptide loading was performed ex vivo and the next day APCs were re-injected into the patients after washing to remove unbound peptide. Patients were vaccinated in the first and second week and thereafter every 4-6 weeks. In 2 of the 5 patients treated, an immune response against the immunising ras peptide could be induced. None of the patients showed evidence of a T-cell response against any of the ras peptides before vaccination. The treatment was well tolerated and could be repeated multiple times in the same patient. Side effects were not observed even if an immunological response against the ras peptide was evident. We conclude that ras peptide vaccination according to the present protocol is safe and may result in a potentially beneficial immune response even in patients with advanced malignant disease.

Adult↗
PubMed1996

Generalized atrophic benign epidermolysis bullosa. Either 180-kd bullous pemphigoid antigen or laminin-5 deficiency.

BACKGROUND: Generalized atrophic benign epidermolysis bullosa (GABEB) is a form of nonlethal junctional epidermolysis bullosa, clinically characterized by generalized blistering after birth, atrophic healing, and incomplete universal atrophic alopecia with onset in childhood. Recently, we discovered a deficiency of the 180-kd bullous pemphigoid antigen (BP180) and a reduced amount of BP180 messenger RNA in three patients with GABEB. It is not yet clear, however, whether GABEB is invariably caused by BP180 deficiency. RESULTS: We examined 18 patients with nonlethal junctional epidermolysis bullosa from unrelated families; nine of these individuals presented with the clinical characteristics of GABEB. Specimens of clinically normal skin obtained from the patients were stained by immunofluorescence with monoclonal antibodies to BP180 and laminin-5. The BP180 epitopes were not expressed in eight patients, all of whom were sharing the typical clinical features of GABEB. In one of the nine patients with GABEB, the BP180 level was sufficient, but the laminin-5 level was reduced. Among the nine patients with junctional epidermolysis bullosa without atrophic alopecia, laminin-5 level was not expressed in one patient, while in the other patients both antigens were normally expressed. CONCLUSIONS: Not all patients with GABEB are deficient in BP180, since some individuals with GABEB only exhibit reduction of the laminin-5 expression. The BP180 deficiency in the skin invariably seems to result in GABEB. Immunofluorescence analysis using monoclonal antibodies against BP180 (and laminin-5) may allow early subtyping, which is of prognostic significance, in children born with junctional epidermolysis bullosa.

Adolescent↗