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J W Bauer

Publications and source records attributed to J W Bauer.

35 records · Page 2Linked to original sources
PubMed1999

[Prenatal diagnosis of recessive hereditary dystrophic epidermolysis bullosa with haplotype analysis of the type VII collagen gene].

DNA-based prenatal testing of the fetal genotype was performed in a family at risk for recurrence of recessive dystrophic epidermolysis bullosa (RDEB). DNA from cultured fibroblasts and leukocytes from the peripheral blood of the previously affected offspring, DNA from parental leukocytes and DNA from fetal tissue obtained by chorionic villus biopsy was analysed by direct PCR amplification of known polymorphic regions within or flanking the type VII collagen gene, the candidate gene in RDEB. One flanking marker (D3S2/Mspl) as well as two intragenic polymorphisms (C7/Mspl, C7/Eco01091) in exons 30 and 84 were informative in this family. Thus, based on the haplotype analysis and the lack of evidence for locus heterogeneity in RDEB, a phenotypically healthy child was predicted. This prediction was confirmed by the birth of a healthy female infant. The study reports successful determination of the fetal genotype by PCR-based prenatal diagnosis in a family at risk for recurrence of severe RDEB.

Adult↗
PubMed1999

Ocular involvement in IgA-epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous disease with frequent ocular involvement, but visual loss is rare. In contrast, EBA patients with predominant IgA autoantibodies more frequently develop severe ocular involvement, which tends to be refractory to therapy. We report two patients with 'IgA-EBA' with ocular involvement. Both initially presented with a generalized bullous disease, and direct immunofluorescence microscopy demonstrated IgA in the basement membrane zone of the skin, and in the conjunctiva and cornea of patient 1. On salt-split patient skin, IgA was found predominantly on the dermal side of the artificial split in both patients. Direct immunoelectron microscopy demonstrated IgA below the lamina densa in close association with the anchoring fibrils in both patients. In patient 1, who had a prolonged course of the disease, the skin disorder responded well to treatment with cyclosporin, but the ocular involvement ended in bilateral blindness despite repeated surgical treatment. In patient 2, the blister formation and scarring conjunctivitis was stopped by a combination of prednisolone and colchicine. These patients show that in subepithelial blistering diseases, early delineation of disease nosology is critical to detect subtypes with severe ocular involvement such as 'IgA-EBA'. In addition, colchicine may be a valuable alternative in the treatment of EBA with ocular involvement.

Adult↗
PubMed1998

A deletion mutation in COL17A1 in five Austrian families with generalized atrophic benign epidermolysis bullosa represents propagation of an ancestral allele.

Patients with generalized atrophic benign epidermolysis bullosa, a usually nonlethal form of junctional epidermolysis bullosa, have generalized blistering, nail dystrophy, patchy alopecia, and dental abnormalities. Skin fragility in most cases is due to mutations in the gene encoding type XVII collagen (COL17A1). Recently, we reported five Austrian families with generalized atrophic benign epidermolysis bullosa who share the same COL17A1 mutation. Affected individuals in three families are homozygous for 4003delTC, whereas those in two others are compound heterozygotes. To determine if the occurrence of 4003delTC in these unrelated families signifies propagation of an ancestral allele or a mutational hot spot, haplotypes were determined for polymorphisms both within and flanking COL17A1. Five intragenic polymorphisms were chosen based on their informativeness. One of these, not previously reported, was 2988 A or C that introduces a new restriction site for Eco0109 I. All the 4003delTC alleles showed the same haplotype for these five polymorphic markers. Fourteen microsatellite polymorphisms were selected based on their high heterozygosity and their location within 10q23-q25 near COL17A1. Three families shared microsatellite polymorphisms covering at most 19 cM, whereas the others shared smaller regions consistent with cross-over events during passage of this mutation through several generations. These results indicate that 4003delTC occurs on a single ancestral allele.

Alleles↗
PubMed1998

Cycloheximide facilitates the identification of aberrant transcripts resulting from a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa.

Patients with generalized atrophic benign epidermolysis bullosa often show decreased expression of type XVII collagen, a transmembrane hemidesmosomal protein encoded by COL17A1. This report documents a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa, and applies a new methodology to define and characterize the resulting mRNA splice variants. Mutational analysis of COL17A1 identified a maternally inherited G-to-T transversion at the -1 position of exon 32. This acceptor splice-site mutation led to the formation of aberrant transcripts present at extremely low levels. Based on our recent finding that cycloheximide stabilized mutant COL17A1 transcripts in keratinocytes homozygous for a frameshift mutation, the effects of the splice-site mutation on splicing of COL17A1 transcripts were determined using reverse transcriptase polymerase chain reaction of total RNA from keratinocytes incubated for 2.5 h in the presence or absence of 10 microg cycloheximide per ml. Using this approach, an abnormally spliced transcript was identified that contains an extra 264 bases upstream from exon 32, resulting in a premature termination codon 27 bp downstream from the cryptic splice site. Three other splice variants, including one derived from the skipping of exon 32, were also identified. These results indicate the usefulness of cycloheximide treatment in evaluating the abnormal processing of mRNA due to splice-site mutations, because: (i) aberrant splicing often generates a premature termination codon, (ii) transcripts with premature termination codons can occur at low or undetectable levels due to nonsense-mediated mRNA decay, and (iii) the levels of these transcripts can be increased by cycloheximide.

Adult↗
PubMed1998

Novel and de novo glycine substitution mutations in the type VII collagen gene (COL7A1) in dystrophic epidermolysis bullosa: implications for genetic counseling.

The dystrophic forms of epidermolysis bullosa (DEB) are due to mutations in the type VII collagen gene (COL7A1). In dominant DEB, a characteristic genetic lesion is a glycine substitution mutation within the collagenous domain of the protein. In this study, we have examined the molecular basis of six new families in which the proband has clinical features and/or ultrastructural findings consistent with DEB. The results revealed a glycine substitution mutation in all six families, four of which are novel and previously unpublished. In three families with clinically unaffected parents, de novo mutations G2043R and G2040V were found. These results emphasize the predominance of glycine substitution mutations in dominant DEB, and indicate that in some cases the phenotype is due to de novo dominant mutations.

Amino Acid Substitution↗
PubMed1997

Premature termination codons are present on both alleles of the bullous pemphigoid antigen 2/type XVII collagen gene in five Austrian families with generalized atrophic benign epidermolysis bullosa.

Patients with generalized atrophic benign epidermolysis bullosa (GABEB), an inherited subepidermal blistering disease, often have no immunologically detectable bullous pemphigoid antigen 2 (BPAG2) in their epidermal basement membrane. Recently, we analyzed the BPAG2 gene (GenBank no. M91669) in an Austrian family with GABEB and identified a homozygous deletion mutation, 4003delTC, that results in a downstream premature termination codon (PTC). This mutation has now been identified in additional descendants, suggesting transmission of this mutant allele through at least six generations. Screening of four other Austrian GABEB families revealed that affected members were homozygous for 4003delTC in two cases and heterozygous in two others. In the latter, mutational analysis identified two novel nonsense mutations, Q1403X and G803X, that were confirmed by restriction endonuclease digestions. Thus, PTCs on both alleles of BPAG2 are present in all of these GABEB families. Immunoprecipitation and northern blot studies of cultured keratinocytes from homozygous GABEB patients show that 4003delTC results in undetectable levels of BPAG2 protein and mRNA-findings consistent with the process of nonsense-mediated mRNA decay. Incubating keratinocytes with cycloheximide increased BPAG2 mRNA to a level detectable by northern analysis. When the latter was used in reverse transcription-PCR studies, the mutation was demonstrated, suggesting that cycloheximide may allow mutational analysis in cases where low transcript levels have previously thwarted RT-PCR studies. These findings account for the absence of BPAG2 in GABEB patients and attest to the importance of this protein in adhesion of epidermis to epidermal basement membrane.

Alleles↗
PubMed1997

Generalized atrophic benign epidermolysis bullosa.

Junctional EB was once considered a uniformly fetal autosomal recessive skin disease. One of the first and best characterized forms of generalized JEB that has a more favorable prognosis was GABEB. Since its initial description in 1976, many additional cases have been compiled, all sharing the features of chronic blistering from birth, nail dystrophy, hair loss, and abnormal teeth. In addition, some patients have large melanocytic nevi that form at sites of prior blisters. The first clues as to the protein defective in these patients was provided by immunofluorescence microscopy studies, which showed absent or decreased expression of type XVII collagen in these patient's epidermal BM. This protein was a promising candidate because it is located in the ultrastructural plane where blisters from in patients with GABEB. It is also the same hemidesmosomal protein against which antibodies are directed in patients with autoimmune blistering diseases: bullous, gestational, and cicatricial pemphigoid. The demonstration of decreased expression of type XVII collagen in patients with GABEB pointed the way to a crucial distinction that could not be based on clinical and histologic findings--that of discriminating infants with GABEB from those with the lethal Herlitz variant of JEB. These two diseases may be differentiated because decreased expression of type XVII collagen is found exclusively in GABEB, whereas decreased expression of laminin 5 is most likely associated with Herlitz JEB. The molecular basis of GABEB has been determined. The immunofluorescence microscopy studies mentioned above directed mutation studies to the COL17A1 gene. Several mutations in COL17A1 have been described in patients with GABEB, almost all of which result in a PTC. As a consequence of the PTC, mutant COL17A1 transcripts are rapidly degraded by nonsense-mediated mRNA decay, blocking production of type XVII collagen from the mutant allele. Heterozygous carriers of the mutation are thus rendered untouched by the mutation. In the homozygous state, however, this results in the absence of this vital adhesion protein, leading to chronic blistering and skin fragility observed in these patients. These studies also significantly increase our knowledge about the normal functions of type XVII collagen. The fact that patients deficient in type XVII collagen have fragile skin attests to the role of this protein in the adhesion of basal keratinocytes to epidermal BM. The severity of GABEB, however, is much less than that observed in patients with a complete deficiency of laminin 5, suggesting that type XVII collagen functions cooperatively with other hemidesmosomal proteins in promoting adhesion. Studies using GABEB keratinocytes will help characterize these kinds of interactions. The ultimate prospect of mutation analysis in these patients is the hope of correcting their genetic defect and curing their disease. Until then, the physician plays an important role in making the diagnosis, providing general supportive skin care, advising avoidance of trauma, treating infections, and supporting the patient's psychosocial development. Further studies of patients with GABEB will lead to new therapeutic approaches, as well as reveal additional complex functions of type XVII collagen not only in skin, but also in hair, teeth, and nails.

Collagen↗
PubMed1993

Histamine induces a gene-specific synthesis regulation of secretogranin II but not of chromogranin A and B in chromaffin cells in a calcium-dependent manner.

The effect of histamine on steady-state mRNA levels of three soluble secretory proteins from chromaffin granules was investigated in cultured bovine adrenal medullary cells. Histamine stimulated secretogranin II mRNA 4-fold, with no or only slight effects on chromogranin A and B transcription. After an initial lag phase, secretogranin II mRNA increased markedly between 4 and 12 h followed by a plateau phase up to 48 h. The effect of histamine on secretogranin II gene-expression was abolished by the H1 receptor antagonist promethazine but not by the H2 blocker cimetidine. The histamine-induced elevation of secretogranin II mRNA was partially reduced by the L-type calcium channel blocker nifedipine, indicating a contribution of extracellular calcium in the second messenger signaling pathway involved. At present, the H1 histaminergic receptor is the first membrane receptor found regulating secretogranin II biosynthesis in chromaffin cells. The selective up-regulation of secretogranin II mRNA but not of chromogranin A and B by histamine is another example illustrating that the synthesis regulation of secretory components co-stored in large vesicles of neuroendocrine cells is specific to the individual gene. Together with results obtained earlier, our data demonstrate a marked variation in the relative composition of peptides secreted from adrenal medulla into circulation following different physiologic conditions.

Adrenal Medulla↗
PubMed1991

Primary structure of bovine chromogranin B deduced from cDNA sequence.

The cDNA sequence of bovine chromogranin B has been determined. Bovine chromogranin B consists of 626 amino acids and contains 16 pairs of basic amino acids which might be used for generation of biological active peptides. A comparison of the amino acid sequences of chromogranin B from various species identifies regions of high homology at the N- and C-termini as well as stretches in the middle of the chromogranin B sequence.

Amino Acid Sequence↗
PubMed1978

Tuning curves and masking functions of auditory-nerve fibers in cat.

Single units of the auditory nerve are maximally sensitive to a given frequency, the so-called characteristic frequency (CF). Tuning curves (functions relating the "threshold" for such units to the frequency of a sinusoidal stimulus) have inspired psychophysical measurements of masked thresholds in humans. At low levels, the results bear a striking resemblance to neural tuning curves, suggesting that a small, homogeneous group of units determine the so-called psychophysical tuning curves. This paper describes physiological measurements modeled after the psychophysical forward-masking paradigm. A masking tone was used to reduce the response in auditory-nerve fibers elicited by a probe tone that followed the masker. The level of the masking tone was varied to maintain a criterion level of responding to the probe. Plotting level of the masker as a function of its frequency yields a fiber-masking function. For low probe-tone levels, fiber-masking functions of low CF fibers and the tips of functions from high CF fibers were similar in shape to tuning curves obtained with single tone bursts. The fiber-masking function depends upon the response criterion and upon the level, duration, and frequency of the probe. Varying the level of the probe can also alter the shape of the fiber-masking function. These results have implications for interpreting psychophysical masking functions.

Acoustic Stimulation↗
PubMed1971

Evoked potential correlates of auditory signal detection.

A long-latency comnponent of the averaged evoked potential recorded from the human scalp varied in close relationship with subjects' perceptual reports in an auditory signal detection task. Detected signals evoked potentials several times larger than did undetected signals, falsely reported signals, or correctly reported nonsignals. The threshold signal intensity at which detection perfornmance exceeded chance levels was identical with concurrently obtained electro-physiological measures of threshold.

Auditory Perception↗
PubMedDate not supplied

Squamous cell carcinoma in junctional and dystrophic epidermolysis bullosa.

We report here on three patients suffering from recessive dystrophic epidermolysis bullosa and one suffering from generalized atrophic benign epidermolysis bullosa, all of whom developed cutaneous squamous cell carcinoma. Our observations and a review of the literature suggest that squamous cell carcinoma in generalized atrophic benign epidermolysis bullosa is very infrequent and has a better outcome compared to skin cancer in recessive dystrophic epidermolysis bullosa. These differences could be explained by the distinct pathophysiology and clinical course of each of these variants of epidermolysis bullosa. In contrast to UV-induced skin cancer, the tumours in epidermolysis bullosa develop on distal extremities at sites of chronic wound healing. The cases reported here underline the exceptional importance of early histopathological assessment of suspicious skin lesions in patients with epidermolysis bullosa.

Adult↗
PubMedDate not supplied

Ocular involvement in anti-epiligrin cicatricial pemphigoid.

PURPOSE: To report an anti-epiligrin cicatricial pemphigoid (AECP) patient with severe ocular involvement and to provide a practical approach to distinguishing AECP patients from those with other subepidermal blistering diseases. METHODS: Techniques included direct and indirect immunofluorescence microscopy, Western blot and immunoprecipitation studies, as well as interdisciplinary examinations of mucous membranes and skin. RESULTS: This study describes a patient with clinical features of cicatricial pemphigoid, circulating anti-basement membrane zone IgG antibodies, and subepidermal blisters. Histopathology and immunofluorescence analysis suggested the diagnosis of a cicatricial pemphigoid-like type of epidermolysis bullosa acquisita. However, Western blot and immunoprecipitation studies demonstrated that the patient's serum contained autoantibodies against laminin 5 alpha3 subunit, leading to the diagnosis of an AECP. CONCLUSION: Since patients with AECP have an increased relative risk for malignant tumors, it is important to distinguish this entity within the spectrum of cicatricial pemphigoid patients by additional studies such as Western blot or immunoprecipitation.

Autoantibodies↗