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Biomedical subjects

F H Herrmann

Publications and source records attributed to F H Herrmann.

At least 37 records · Page 2Linked to original sources
PubMed1999

Severe clinical expression in X-linked Emery-Dreifuss muscular dystrophy.

X-linked Emery-Dreifuss muscular dystrophy (EDMD) is a relatively rare benign neuromuscular disorder which can vary remarkably in onset, course and severity. In the present study, a TCTAC deletion spanning the nucleotides 631-635 of the emerin gene caused an unusually severe disease phenotype including loss of ambulation and severe muscle wasting in two affected brothers. The same mutation has been reported previously in an unrelated family showing a significantly milder phenotype. The interfamilial heterogeneity in distribution and in severity of the features in the two families point to environmental or genetic modification as the cause of clinical variability in Emery-Dreifuss muscular dystrophy.

Adolescent↗
PubMed1999

Different numerical chromosomal aberrations detected by FISH in oropharyngeal, hypopharyngeal and laryngeal squamous cell carcinoma.

AIMS: Little information is available about stage- or site-specific chromosomal aberrations in head and neck squamous cell carcinoma (HNSCC). We tried to identify whether different patterns of chromosomal gain or loss in squamous cell carcinomas were associated with different stages or head and neck sites. METHODS AND RESULTS: We investigated isolated interphase cells from paraffin sections of 5 3 squamous cell carcinomas of the head and neck region by fluorescence in situ hybridization techniques. We used centromeric DNA probes for chromosomes 1, 3, 4, 6, 7, 9, 10, 11, 12, 15, 17, 18, X and Y. The majority of tumour samples showed aneuploidy for most chromosomes analysed. We were able to find differences in the chromosomal aberrations between the tumour sites and stages of the HNSCC investigated. The main numerical chromosomal abnormalities were an under-representation of chromosomes 3 (26%), 6 (17%), 9 (26%), 10 (23%) and 18 (32%). The Y chromosome was lost in 53% of male tumours. A loss of chromosomes 3 and 10 was detected mostly in laryngeal SCC (39% and 30%, respectively); the under-representation of chromosome 9 was predominantly seen in oropharyngeal SCC (54%) and a copy number decrease of chromosomes 18 was found in 57% of hypopharyngeal tumours. CONCLUSION: Although the number of tumour samples investigated is rather low, our results suggest that the different tumour sites of HNSCC may also show different patterns of chromosomal changes.

Adult↗
PubMed1999

Molecular analysis of hemophilia B in Poland: 12 novel mutations of the factor IX gene.

We examined the molecular basis of factor IX deficiency in 53 unrelated Polish patients with hemophilia B. Heteroduplex analysis and direct sequencing of polymerase chain reaction (PCR) products were applied to identify the gene defect. Forty-three different point mutations were detected in the factor IX gene of 47 patients. There were 29 missense mutations, 9 nonsense mutations, 4 splice site mutations and 1 point mutation in the promoter region. Twelve mutations were novel. The results of this study emphasize a very high degree of heterogeneity of hemophilia B.

Adolescent↗
PubMed1998

An increased frequency of numerical chromosomal abnormalities and 1p36 deletions in isolated cells from paraffin sections of malignant melanomas by means of interphase cytogenetics.

At present, little information is available on tumor and stage-specific chromosomal aberrations in malignant melanoma. Therefore, we applied fluorescence in situ hybridization on isolated interphase cells from paraffin sections of 25 cases of malignant melanomas, comprising 17 primary tumors (PTs) and 8 metastases (MTs) in various anatomical sites. We used centromeric probes for chromosomes 1, 7, 9, 10, 11, 12, 15, 17, 18, X, and Y and a midisatellite probe localized in 1p36. Four of the PTs and 5 of the MTs showed polyploidy for all applied probes. The most frequent type of numerical aberration was an overrepresentation of chromosomes 1 (3 PTs, 5 MTs) and 7 (3 PTs, 1 MT), and an underrepresentation of chromosomes 9 (3 PTs) and 10 (6 PTs, 5 MTs). The Y chromosome was lost in all male tumors. In addition, we observed monosomy 11, 12, 15, 17 or 18, and trisomy 12 or 17. Only 1 PT showed no aberrations for any applied DNA probe. A deletion in the near-telomeric region of 1p36 was found surprisingly often (9 PTs, 7 MTs). Our results suggest that the loss of gene(s) in this region is an important event in the pathogenesis of malignant melanoma of the skin.

Adult↗
PubMed1998

In vivo evidence for compromised phenylalanine metabolism in vitiligo.

Human epidermal melanocytes and keratinocytes express mRNA for all enzymes involved in de novo synthesis/recycling of the cofactor (6R) L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4) in normal healthy individuals. An enhanced epidermal de novo synthesis was identified in association with decreased epidermal phenylalanine hydroxylase and 4a carbinolamine dehydratase in patients with vitiligo. The latter event leads to an accumulation of the nonenzymatic isomer (7R) L-erythro 5,6,7,8 tetrahydrobiopterin (7BH4) inhibiting phenylalanine hydroxylase (PAH) with an apparent Ki = 10(-6) M. One consequence of decreased epidermal PAH activities would be a build-up of L-phenylalanine. To substantiate this consideration, FT-Raman spectroscopy was utilised to study in vivo total phenylalanine levels at 1004 cm-1 in involved and uninvolved skin of 23 patients with vitiligo, showing in all cases increased levels of phenylalanine in involved compared to uninvolved skin of the same individual. Additionally the peripheral blood L-phenylalanine turnover was determined over time after a single oral loading with L-phenylalanine in 32 patients (100 mg/kg body weight). All patients demonstrated slower kinetics from L-phenylalanine to L-tyrosine, but 41% of the group showed significantly slower kinetics under these conditions. None of the patients presented peripheral hyperphenylalaninemia without loading. Our results demonstrate for the first time a phenylalanine build-up in the involved epidermis of patients with vitiligo. These data support the earlier observation of a defective epidermal pterin metabolism in this disease.

Adolescent↗
PubMed1998

A de novo translocation 46,X,t(X;15) causing haemophilia B in a girl: a case report.

Haemophilia B is an X-linked recessive bleeding disorder caused by mutations in the factor IX gene with an incidence of 1:25000-30000. Usually female carriers are clinically normal, and severe phenotypic expression of the disease in females is extremely rare. In this report we describe a girl with a clinically severe course of haemophilia B who had no signs of Turner syndrome or any other dysmorphic features. Cytogenetic and molecular studies in the patient and her parents showed a de novo translocation 46,X,t(X;15)(q27.1;p11.2) in the patient, indicating a possible break near the factor IX gene. The structurally normal X chromosome was late replicating and inactivated in all metaphases as shown by high-resolution R-banding. By fluorescence in situ hybridization (FISH) with YAC and cosmid probes we could further characterize the breakpoint region on the X chromosome and the involvement of the factor IX gene.

Adult↗
PubMed1998

Differences in chromosomal aberrations between nodular and superficial spreading malignant melanoma detected by interphase cytogenetics.

At present, little information is available on specific chromosomal aberrations in malignant melanomas of different subtypes and different growth behaviors. Therefore, we have applied fluorescence in situ hybridization on isolated interphase cells from paraffin sections of 79 primary tumors of malignant melanomas: 47 nodular melanomas and 32 superficial spreading melanomas in various stages. We used centromeric probes for the chromosomes 1, 4, 6, 7, 9, 10, 11, 12, 15, 17, 18, X, and Y and a midisatellite probe localized in 1p36. The number of chromosomal aberrations and the ploidy of the cells rose with the tumor stage in both subtypes, although in superficial spreading melanomas, fewer chromosomal abnormalities were detectable than in nodular melanomas. A deletion in 1p36 could only be found in nodular melanomas (mostly in higher tumor stages), not in superficial spreading melanomas. Our results show that the different histologic subtypes of malignant melanoma of the skin differ also in their chromosomal aberrations. In addition, it seems that there may be a correlation between the growth characteristics and putative tumor suppressor genes on 1p36.

Adult↗
PubMed1997

Six novel mutations in the emerin gene causing X-linked Emery-Dreifuss muscular dystrophy.

Mutations in the emerin gene, also referred to as the STA- or EMD-gene, have been found to be the cause of X-linked Emery-Dreifuss muscular dystrophy (EMD). For the present study an optimized set of primers was designed to amplify and sequence each of the six emerin gene exons, including the intron/exon boundaries. All emerin gene exons of 30 unrelated EMD patients have been screened by heteroduplex analysis. Aberrant patterns of single exons were found in seven patients. Direct sequencing of the respective exons revealed six novel mutations distributed in the promotor region and exons 3-6 (delta nt -19 to -40; delta AG nt 620-621; ins A nt 895; delta AT nt 908-909; C-->A nt 1420; ins TA nt 1570). By this study, the first mutations in the promotor region and in exon 5 have been identified. Each of the 25 mutations that have been described so far, including those from the present study, abolishes the synthesis of functional emerin. The mutations were submitted to the EMD Mutation database (http://www.path.cam.ac.uk/emd).

Base Sequence↗
PubMed1997

Prevalence of factor V Leiden mutation in various populations.

Resistance to activated protein C (APC) is the most common inherited risk factor for venous thrombosis. Most cases of APC resistance are caused by the point mutation nt 1691 G-A in factor V gene, referred to as factor V Leiden mutation. As initially shown in a Dutch population, this mutation has a carrier rate of 2.9%, the most frequent genetic disposition for thrombophilia and deep venous thrombosis. By large-scale epidemiological studies we have determined the prevalence of factor V Leiden mutation in populations from Poland (200), Argentina (215), Venezuela (126), Costa Rica (196), and India (150). The prevalences have been estimated for Poland (Warsaw) 5.0%, Argentina (Buenos Aires) 5.1%, Venezuela (Valencia) 1.6%, Costa Rica (San José) 2.0%, and India (Punjab) 1.3%. Based on worldwide distribution, it can be hypothesized that the factor V Leiden mutation has originated and accumulated in central European Caucasians and spread over the world by migration.

Argentina↗
PubMed1997

Direct molecular genetic diagnosis and heterozygote identification in X-linked Emery-Dreifuss muscular dystrophy by heteroduplex analysis.

X-linked Emery-Dreifuss muscular dystrophy (EMD) is a very rare, relatively benign muscle disorder. The disease is associated with potentially lethal cardiac arrhythmias in affected males and some heterozygous females. X-linked EMD can be genetically distinguished from phenotypically similar autosomal EMD. Heterogenic mutations are identified as the cause of X-linked EMD. We introduced heteroduplex analysis to follow the segregation of heterogenic emerin gene mutations in the families of six unrelated EMD patients. Heteroduplex analysis was proved to be a simple, fast and reliable tool for direct molecular genetic diagnosis of EMD in male patients and identification of heterozygotes even in families where affected males are not available as index cases.

DNA Mutational Analysis↗
PubMed1997

Haemophilia B in female twins caused by a point mutation in one factor IX gene and nonrandom inactivation patterns of the X-chromosomes.

Haemophilia B is a X-linked recessive bleeding disorder with an incidence of 1:25,000-30,000 male birth. Usually female carriers are clinically normal. Phenotypic expression of the disease in female carriers is extremely rare. We describe cytogenetically inconspicuous female identical twins both with factor IX levels below 2%, prolonged bleeding after venipuncture as well as haematomas after intramuscular injections. The father, suffering from a severe haemophilia B, is deceased. By sequencing one point mutation was characterized in heterozygote condition in the factor IX gene of the probands at nt 17678. This mutation leads to the substitution cystein 88 to tyrosine in the growth factor domain of the factor IX. Investigation of the X-chromosomal inactivation by comparison of methylation patterns of genomic DNA at locus DXS255 after digestion with Pst I and Pst I +Hha I and hybridisation with the probe M27beta indicated a nonrandom pattern of X-chromosomal inactivation in the twins. In both girls, only the paternal X-chromosome was the active one leading to the phenotypic expression of haemophilia in the female carriers.

Blood Coagulation Tests↗
PubMed1994

Mutations of the iduronate-2-sulfatase (IDS) gene in patients with Hunter syndrome (mucopolysaccharidosis II).

Genomic DNA and cDNA from fibroblasts from nine unrelated German patients with X-linked iduronate-2-sulfatase (IDS) deficiency showing variable clinical manifestation were screened for point mutations and small structural aberrations. Direct sequencing revealed a splice mutation skipping exon A, one nonsense mutation, and five missense mutations concerning the exons B, F and I of the IDS gene. Several novel missense mutations were found: A68E, S426X, I485R, Q293H, and D478G. One of the point mutations eliminating a recognition site for the restriction enzyme MspI was used as a direct marker for a prenatal diagnosis. A relationship between type of mutation and clinical picture could not be recognized.

Female↗
PubMed1993

Biochemical and immunological characterization of X-linked ichthyosis.

An immunoquantification protocol based on an enzyme-linked immunosorbent assay was developed to measure the abundance of the microsomal enzyme steroid sulphatase (STS). The two-step sandwich immunoassay is sufficiently sensitive to detect 100-200 pg purified steroid sulphatase in a 50-microliters sample. The steroid sulphatase content in fibroblast, leukocyte and placental extracts correlates with the steroid sulphatase activity in these extracts. No steroid sulphatase protein was found in approximately 350 micrograms plasma proteins from a normal person. In three of four X-linked ichthyosis patients a complete gene deletion was found by Southern hybridization with the full-length STS cDNA as probe. Neither steroid sulphatase protein nor enzymatic activity was found in fibroblast extracts of these three patients. In a fibroblast extract of another X-linked ichthyosis patient, which had a normal Southern blotting pattern, no immunoreactive protein was detected. Residual activity of steroid sulphatase was also not found after prolonged incubation of this fibroblast extract with the natural substrate oestrone sulphate.

Arylsulfatases↗