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Helmut Hintner

Publications and source records attributed to Helmut Hintner.

13 recordsLinked to original sources
PubMed2006

Ribosomal proteins Rpl10 and Rps6 are potent regulators of yeast replicative life span.

The yeast ribosome is composed of two subunits, the large 60S subunit (LSU) and the small 40S subunit (SSU) and harbors 78 ribosomal proteins (RPs), 59 of which are encoded by duplicate genes. Recently, deletions of the LSU paralogs RPL31A and RPL6B were found to increase significantly yeast replicative life span (RLS). RPs Rpl10 and Rps6 are known translational regulators. Here, we report that heterozygosity for rpl10Delta but not for rpl25Delta, both LSU single copy RP genes, increased RLS by 24%. Deletion of the SSU RPS6B paralog, but not of the RPS6A paralog increased replicative life span robustly by 45%, while deletion of both the SSU RPS18A, and RPS18B paralogs increased RLS moderately, but significantly by 15%. Altering the gene dosage of RPL10 reduced the translating ribosome population, whereas deletion of the RPS6A, RPS6B, RPS18A, and RPS18B paralogs produced a large shift in free ribosomal subunit stoichiometry. We observed a reduction in growth rate in all deletion strains and reduced cell size in the SSU RPS6B, RPS6A, and RPS18B deletion strains. Thus, reduction of gene dosage of RP genes belonging to both the 60S and the 40S subunit affect lifespan, possibly altering the aging process by modulation of translation.

Cell Count↗
PubMed2006

Novel KIND1 gene mutation in Kindler syndrome with severe gastrointestinal tract involvement.

BACKGROUND: Kindler syndrome (online Mendelian Inheritance in Man No. 173650) is an autosomal recessive genodermatosis characterized by acral trauma-induced blistering that improves with age and by progressive poikiloderma in later life. Other clinical features include photosensitivity, webbing of the fingers and toes, nail dystrophy, periodontal disease, and mucosal alterations. Aside from esophageal or anal stenosis, gastrointestinal tract involvement seems to be rare in Kindler syndrome. Recently, mutations in the KIND1 gene that encodes for the membrane-associated protein kindlin-1 have been identified. Kindlin-1 links the actin cytoskeleton to the extracellular matrix and is supposed to have cell-signaling functions owing to different functional domains. In particular, a domain with high homology to 4.1/ezrin/radixin/moesin (FERM) proteins is closely related to the sequences of talin that mediate integrin binding and therefore may play a role in integrin-dependent processes such as cell growth, differentiation, and apoptosis. OBSERVATION: Complete loss of this multifunctional protein in our patient with Kindler syndrome resulted in severe gastrointestinal tract involvement with hemorrhagic colitis. Mucosa of the descending and sigmoid colon and the rectum showed erosions and ulcers with pseudomembranous alterations of an overall highly vulnerable mucosa. Mutation analysis revealed a homozygous status for the novel mutation 20/21delTT in exon 2 of the KIND1 gene resulting in a preterminal stop codon creating a nonfunctional peptide 17 amino acids in length. CONCLUSION: Because of our experience with this and another patient, we propose that gastrointestinal tract involvement should be looked at more frequently in Kindler syndrome.

Adult↗
PubMed2006

Haploinsufficiency due to deletion within the 3'-UTR of C1-INH-gene associated with hereditary angioedema.

PURPOSE: Sequences within the non-coding 3'UTR (untranslated region) of genes were reported to be involved in the regulation of gene expression by modifying pathways of (co)transcription, post-transcriptional processing and RNA transport. However, direct biological evidence (i.e., knock-out models) is sparse. This report intends to correlate the first reported alteration within the 3'UTR of the C1 inhibitor (C1-INH) gene with clinical presentation of hereditary angioedema (HAE). METHODS AND RESULTS: Direct sequencing of genomic DNA revealed in all affected members of a family suffering from HAE a heterozygous 155 bp deletion 100 bp downstream of the physiological stop-codon in exon 8. A substantial reduction of both mRNA as well as C1-INH protein expression was revealed by RT-PCR and nephelometry, respectively. CONCLUSION: We suppose that the mutation within the 3'UTR interferes with integral pathways of gene expression leading to pathogenic haploinsufficiency in this family.

3' Untranslated Regions↗
PubMed2005

Prospective, randomized, multicenter, double-blind placebo-controlled trial comparing adjuvant interferon alfa and isotretinoin with interferon alfa alone in stage IIA and IIB melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group.

PURPOSE: The combination of interferon alfa (IFNalpha) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines, but it remained unclear whether this combination is more effective than IFNalpha alone in patients with metastatic melanoma. We evaluated safety and efficacy of IFNalpha and isotretinoin compared with IFNalpha alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB. PATIENTS AND METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, 407 melanoma patients in stage IIA (301 patients) and IIB (106 patients) were randomly assigned to either IFNalpha and isotretinoin (isotretinoin group; 206 patients) or IFNalpha and placebo (placebo group; 201 patients) after excision of the primary tumor. IFNalpha was administered three times a week at a dose of 3 million units subcutaneously for 24 months. Isotretinoin at a dose of 20 mg for patients < or = 73 kg, 30 mg for patients greater than 73 kg, or placebo daily for 24 months. RESULTS: A scheduled interim analysis revealed no significant differences in survival rates, with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55% (95% CI, 46% to 65%) and 67% (95% CI, 59% to 75%), respectively, and overall 5-year survival rates of 76% (95% CI, 67% to 84%) and 81% (95% CI, 74% to 88%), respectively. The trial was stopped for futility. CONCLUSION: The addition of isotretinoin to an adjuvant treatment of low-dose IFNalpha in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended.

Adolescent↗
PubMed2005

[Dental alterations in junctional epidermolysis bullosa--report of a patient with a mutation in the LAMB3-gene].

During early odontogenesis the basement membrane is known to be important in epithelio-mesenchymal interactions. Mutations in the gene of one of the major structural proteins of the basement membrane such as laminin 5 might therefore be expected either to seriously compromise ameloblast differentiation and/ or interfere with normal basement-membrane formation and degradation and thus the binding of the ameloblasts to their underlying matrix. Teeth of patients suffering from junctional epidermolysis bullosa (JEB) can be severely affected by abnormal dental development and generalized or focal enamel hypoplasia. Those changes are found in 100% of individuals with JEB but the expression is variable. Beside the quantitative alterations, changes in the prismatic structure and orientation of enamel crystals are described. In addition JEB is associated with an increased risk for dental caries, caused by developmentally compromised enamel and external factors such as difficulties in maintaining oral hygiene because of oral lesions or a softer and more refined high caloric diet. Dental care includes three main strategies: Prevention by consequent oral hygiene and reduction of cariogenic nutrition is of paramount importance to minimize caries development; the restoration of enamel and dentin defects with fillings and stainless steel crowns to guarantee structure and function of teeth; and extractions of most severely affected teeth with osteolytic foci to remove continuous sources of oral infections.

Adult↗
PubMed2004

Identification of vitamin D target genes in human keratinocytes by subtractive screening.

1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2) D(3)) imposes cell cycle block in late G1 phase in cultured human keratinocytes. We wanted to identify early vitamin D target genes using a subtractive screening approach. Human foreskin keratinocytes were grown to about 70% confluence, treated with 2 x 10(-7) M 1alpha,25(OH)(2) D(3) or left untreated and RNA from both populations were isolated after 22h of incubation. cDNA was synthesised and cloned into plasmid vectors. For screening of the libraries, cDNA was amplified in vitro using T7 RNA polymerase and then the amplified RNA (driver, control population) and single stranded cDNA (tester) were used for subtractive hybridisation. Heterohybrids were then separated from single stranded nucleotides using a hydroxyapatite column. The radiolabeled single stranded cDNA was used for screening a colony blot. Positive clones were rescreened, plasmid DNA was isolated and used for verifying the results by Northern blot analysis, using RNA isolated from untreated keratinocytes, as well as RNA isolated after 6h, 12h and 24h of vitamin D treatment.

Blotting, Northern↗
PubMed2004

Analysis of the LAMB3 gene in a junctional epidermolysis bullosa patient reveals exonic splicing and allele-specific nonsense-mediated mRNA decay.

How splicing, the process of intron removal in pre-messenger RNA (mRNA), is carried out with such fidelity in human cells is still not understood, although some general rules are being proposed mainly by in vitro experiments. These rules are currently being redefined by analysis of splicing mechanisms in patients presenting splicing defects. We analysed material of a patient suffering from junctional epidermolysis bullosa, a heritable blistering skin disease. Absence of laminin-5 protein together with hypoplastic hemidesmosomes at the dermo-epidermal junction in the patient's skin was shown by immunohistochemical analysis and immunoelectron microscopy. Subsequent DNA analysis revealed heterozygosity for the mutations R635X and 3009C-->T in the LAMB3 gene. The latter did not alter codon translation, but introduced an exonic splice site in exon 20. Interestingly, this exonic splice site, which presented a splice score of only 68.6, was preferentially used by the spliceosome over the wild-type splice site at the exon 20-intron 20 border, which showed a splice score of 92.2. LAMB3 mRNA was still detectable in RT-PCR analysis although the aberrantly spliced mRNA leads to a stop codon in exon 21, 5' of the commonly assumed 3' border for nonsense-mediated mRNA decay. These results describe an exception to the proposed rules of pre-mRNA splicing and RNA degradation.

Adult↗
PubMed2004

[Systemic ALlambda amyloidosis associated with vascular fragility].

A 63-year-old patient had experienced bilateral spontaneous periorbital hemorrhage for one year. After hospitalization because of recurring hemoptysis, biopsies of skin and colon revealed systemic ALlambda amyloidosis. In addition, the heart and lungs appeared to be involved. Monoclonal gammopathy was excluded by a normal plasma cell count and a polyclonal expression pattern in a bone marrow sample and by radiographic examination. The patient was treated with a relatively non-aggressive regimen of melphalan and prednisolone monthly with careful hematologic monitoring. This approach led to a significant improvement in relevant parameters. Recent advances in diagnosis, monitoring and therapy have made it easier to manage patients with amyloidosis with their poor prognosis.

Amyloidosis↗
PubMed2003

Photoperiod modulates melanoma growth in C57BL/6 mice.

Seasonal variations can be found in almost any parameter of an organism's biochemistry, physiology, endocrinology, and behaviour. This phenomenon, generally called photoperiodism, results from one of the major functions of the circadian system, i.e. the translation of environmental information into rhythmic intraorganismic signals, which then regulate or influence physiology and pathology. We induced melanoma in three groups of syngeneic C57BL/6 mice synchronised to different photoperiods (8, 12, or 18 h of light within 24-h days) by subcutaneous injections of HFH18 melanoma cell suspensions. All animals from all three photoperiodic groups developed exponentially growing tumors. The average tumor volume on day 31 post injection was significantly smaller in animals exposed to light/dark conditions (LD) 8 : 16 h as compared with animals held in LD 18 : 6 h and intermediate in animals from the equinox group. These results indicate that C57BL/6 mice react to photoperiod, which can exert a significant effect on tumor growth.

Animals↗
PubMed2003

Feline orthopoxvirus infection transmitted from cat to human.

We report the case of a 56-year-old female patient who presented with an inflamed, ulcerated lesion on the left side of her neck after contact (scratch) with a cat living in the patient's house. Satellite lesions developed despite local treatment and parenteral clindamycin. Histopatholgic examination and the Tzanck test showed evidence of a viral infection. Subsequent transmission electron microscopy of scrap tissue and material from a fresh pustule exhibited multiple typical poxvirus particles, predominantly in remnants of scaled-off layers of degenerated keratinocytes, and virus particles in intermingled phagocytes, leading to the diagnosis of feline Orthopoxvirus (cowpox virus) infection. These results were verified by polymerase chain reaction and sequencing. Concern has been raised as to whether discontinuation of smallpox vaccine would cause an increase in Orthopoxvirus infection, but this has not yet shown to be the case.

Acyclovir↗
PubMed2003

Pathogenic mechanisms in epidermolysis bullosa naevi.

Epidermolysis bullosa naevi are large, eruptive melanocytic naevi which frequently arise in areas of former blisters in patients suffering from inherited epidermolysis bullosa. Morphologically, these naevi are similar to malignant melanoma, although so far no malignant transformation has been observed. To investigate the pathogenesis of these moles we documented their clinical evolution and their histopathological and immunocytological characteristics in three patients with epidermolysis bullosa. Clinically, we observed signs of malignant transformation, such as explosive growth and the occurrence of satellite lesions of epidermolysis bullosa naevi. However, malignant melanoma was excluded by histopathological evaluation. In addition, we evaluated the concentrations of various factors known to stimulate melanocyte growth in blister fluid. Human interleukin 8, basic fibroblast growth factor, human hepatocyte growth factor, GM-CSF, leukotriene B4 and prostaglandin E2 revealed concentrations comparable with the levels in inflammatory blisters. We were able to detect individual melanocytes/naevus cells in blister fluid from a blister over an epidermolysis bullosa naevus. The factors detected in the blister fluid might therefore promote the proliferation, migration and melanogenesis of disconnected melanocytes/naevus cells representing the basis of the highly dynamic appearance of epidermolysis bullosa naevi.

Biological Factors↗
PubMed2002

Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma.

Transgenic mouse models have provided evidence that activation of the zinc-finger transcription factor GLI1 by Hedgehog (Hh)-signalling is a key step in the initiation of the tumorigenic programme leading to Basal Cell Carcinoma (BCC). However, the downstream events underlying Hh/GLI-induced BCC development are still obscure. Using in vitro model systems to analyse the effect of Hh/GLI-signalling in human keratinocytes, we identified a positive feedback mechanism involving the zinc finger transcription factors GLI1 and GLI2. Expression of GLI1 in human keratinocytes induced the transcriptional activator isoforms GLI2alpha and GLI2beta. Both isoforms were also shown to be expressed at elevated levels in 21 BCCs compared to normal skin. Detailed time course experiments monitoring the transcriptional response of keratinocytes either to GLI1 or to GLI2 suggest that GLI1 is a direct target of GLI2, while activation of GLI2 by GLI1 is likely to be indirect. Furthermore, expression of either GLI2 or GLI1 led to an increase in DNA-synthesis in confluent human keratinocytes. Taken together, these results suggest an important role of the positive GLI1-GLI2 feedback loop in Hh-mediated epidermal cell proliferation.

Alkaline Phosphatase↗