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Biomedical subjects

D Hohl

Publications and source records attributed to D Hohl.

12 recordsLinked to original sources
PubMed1992

The human loricrin gene.

Loricrin is the major protein component of the cornified cell envelope of terminally differentiated mammalian epidermal (stratum corneum) cells. Using a specific human cDNA clone, we have isolated and characterized the human loricrin gene. We show that it has a very simple structure of a single intron of 1188 base pairs (bp) in the 5'-untranslated region; there are no introns in coding sequences. By use of rodent-human somatic cell hybrids, followed by in situ hybridization with a biotin-labeled genomic DNA clone, the single-copy gene maps to chromosome location 1q21. Polymerase chain reaction analyses of genomic DNAs from different individuals show that human loricrin consists of two allelic size variants, due to sequence variations in its second glycine loop domain, and these variants segregate in the human population by normal Mendelian mechanisms. Furthermore, there are multiple sequence variants within these two size class alleles due to various deletions of 12 bp (4 amino acids) in the major loop of this glycine loop domain. By use of a specific loricrin antibody, we show by immunogold electron microscopy that loricrin initially appears in the granular layer of human epidermis and forms composite keratohyalin granules with profilaggrin, but localizes to the cell periphery (cell envelope) of fully differentiated stratum corneum cells.

Amino Acid Sequence↗
PubMed1992

Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis.

Epidermolytic hyperkeratosis is a hereditary skin disorder characterized by blistering and a marked thickening of the stratum corneum. In one family, affected individuals exhibited a mutation in the highly conserved carboxyl terminal of the rod domain of keratin 1. In two other families, affected individuals had mutations in the highly conserved amino terminal of the rod domain of keratin 10. Structural analysis of these mutations predicts that heterodimer formation would be unaffected, although filament assembly and elongation would be severely compromised. These data imply that an intact keratin intermediate filament network is required for the maintenance of both cellular and tissue integrity.

Amino Acid Sequence↗
PubMed1992

A prospective study of skeletal changes during short-term acitretin therapy.

We prospectively analyzed skeletal changes of 16 patients who were treated with acitretin for various disorders of keratinization at doses of 10-50 mg/day (overall mean 0.4 mg/kg/day) for 7-12 months (mean 11.4 months). Skeletal changes from pretherapy findings were observed in 5 patients. In 4 of 5 patients they appeared to be linked to a preexisting degenerative pathology and could not be attributed to acitretin therapy. However, in 1 patient a spinal osseous side effect could not be excluded. No retinoid-induced extraspinal tendon or ligament calcifications were observed.

Acitretin↗
PubMed1992

[Erythema nodosum and AIDS].

We report on a patient with AIDS who developed erythema nodosum, an association that has not previously been reported. Extensive clinical and laboratory investigations disclosed no obvious origin of erythema nodosum apart from HIV infection with disseminated Kaposi sarcoma.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Characterization of human loricrin. Structure and function of a new class of epidermal cell envelope proteins.

We have isolated and characterized a full-length cDNA clone encoding human loricrin. Curiously, this protein displays major differences from the recently described mouse loricrin (Mehrel, T., Hohl, D., Nakazawa, H., Rothnagel, J.A., Longley, M.A., Bundman, D., Cheng, C.K., Lichti, U., Bisher, M.E., Steven, A. C., Steinert, P.M., Yuspa, S.H., and Roop, D.R. (1990) Cell 61, 1103-1112). Although both proteins are glycine-serine-cysteine-rich, the sequences have not been conserved. However, analysis of the sequences reveals a common motif of quasi-peptide repeats of an aliphatic or aromatic amino acid residue followed by several glycine and/or serine and cysteine residues. These sequences are interspersed and flanked by short glutamine- or glutamine/lysine-rich peptides. Thus loricrins consist of a family of cell envelope proteins of highly variable sequences that nevertheless retain common structural elements. We show that unlike all other putative protein components of the cell envelope, loricrins are highly insoluble, due at least in part to cross-linking by disulfide bonds. Furthermore, we have isolated four peptides from purified human cell envelopes that contain recognizable loricrin sequences and which are cross-linked by the N epsilon-(gamma-glutamyl)lysine isodipeptide bond. The presence of such bonds thus affords an explanation for the extraordinary insolubility of loricrin by cross-linking to the cell envelope and can also explain the low steady-state levels of monomeric loricrin in cytoskeletal extracts of epidermis. This study represents the first report of this isodipeptide cross-link in a protein component of the cornified cell envelope. We propose a model for the structure of loricrin in which (i) the unusual glycine-serine-rich sequences adopt a flexible loop conformation, indexed on the recurrent aliphatic residues; (ii) inter- or intramolecular isodipeptide and disulfide cross-links induce or stabilize folding of loricrin so as to form a more compact rosette-like structure; and (iii) the presence of the flexible glycine-rich loops necessarily will impact a flexible character to the cell envelope and entire epithelium.

Amino Acid Sequence↗
PubMed1991

Transcription of the human loricrin gene in vitro is induced by calcium and cell density and suppressed by retinoic acid.

We have previously shown that loricrin is a major component of the cornified cell envelope (CE) expressed late in epidermal differentiation in the granular layers of normal skin. Normal human keratinocytes were cultured under various conditions and loricrin mRNA levels were assessed at various time points. Only Ca++ concentrations above 0.1 mM Ca++ were permissive for the expression of lori-crin mRNA. Maximal mRNA levels were found at 0.35 mM Ca++ and a critical cell density appeared to be required for optimal accumulation of loricrin transcripts. Retinoic acid (RA) at 10(-7) to 10(-9) M completely blocked Ca+(+)-induced loricrin mRNA synthesis when applied simultaneously. Furthermore, addition of RA to cultures already exposed to higher Ca++ levels resulted in the complete loss of loricrin mRNA within 48-72 h. So far, no other components of the CE have been shown to be suppressed by RA. However, similar patterns of expression were reported for filaggrin, a matrix protein also expressed late in epidermal differentiation. Therefore, we compared the mRNA levels of loricrin and filaggrin and found them to change in parallel in response to the various culture conditions. These results suggest that Ca++, cell density, and RA are crucial regulators of loricrin expression in vitro and that the transcriptional control of loricrin and filaggrin expression in the epidermis are closely coordinated.

Blotting, Northern↗
PubMed1991

Nodular cutaneous mucinosis--an unusual multiple type of euthyreotic focal mucinosis.

A 32-year-old Turkish man with a progressive appearance of indolent, skin-colored nodules on the trunk and proximal extremities is presented. Clinical and laboratory examinations did not reveal any other relevant abnormalities. Histological specimens showed focal, ill-defined depositions of acid mucopolysaccharides mainly in the reticular dermis. Collagen fibers were split up and separated. Ultrastructurally, activated fibroblasts and an increased synthesis of collagen fibrils and elastic microfibrils as well as numerous macrophages were noticed. Diagnostically, an unusual multiple type of cutaneous focal mucinosis is most likely.

Adult↗
PubMed1990

Identification of a major keratinocyte cell envelope protein, loricrin.

During epidermal cell cornification, the deposition of a layer of covalently cross-linked protein on the cytoplasmic face of the plasma membrane forms the cell envelope. We have isolated and characterized cDNA clones encoding a major differentiation product of mouse epidermal cells, which has an amino acid composition similar to that of purified cell envelopes. Transcripts of this gene are restricted to the granular layer and are as abundant as the differentiation-specific keratins, K1 and K10. An antiserum against a C-terminal peptide localizes this protein in discrete granules in the stratum granulosum and subsequently at the periphery of stratum corneum cells. Immunofluorescence and immunoelectron microscopy detect this epitope only on the inner surface of purified cell envelopes. Taken together, these results suggest that it is a major component of cell envelopes. On the basis of its presumed function, this protein is named loricrin.

Amino Acid Sequence↗
PubMed1990

Cornified cell envelope.

The cornified cell envelope (CE) is a highly insoluble structure on the inside of the plasma membrane of terminally differentiated keratinocytes. The cellular and molecular biology of the CE is outlined and new areas of research involving the CE are reviewed focussing on morphological and biochemical connections, the sequential gene expression during terminal differentiation, the interaction of lipids and proteins forming the epidermal barrier, the cysteine-rich pool of proteins in the epidermis as well as the molecular cloning and/or characterization of major components of the CE.

Amino Acids↗
PubMed1990

[A new star in the heavens of epidermal proteins: loricrin--what is it?].

A cDNA clone, encoding for a major component of the cornified cell envelope now termed loricrin, was isolated by cross-hybridization with the end domains of keratin 1 and 10. Loricrin is expressed very late in terminal epidermal differentiation in the upper stratum granulosum and is identical to the sulfur-rich component of the single type keratohyaline granule. Moreover, loricrin appears later to become cross-linked by the formation of glutamyl-lysyl-isopeptide bonds and thereby incorporated as a major component into the cornified cell envelope. In vivo, loricrin is expressed in all mammalian stratified epithelia tested so far. However, the highest levels of expression are found in humid tissues such as newborn epidermis, the epithelia of oral and anal mucosa, esophagus, foreskin, vagina and the epidermal parts of sweat ducts.

Cell Differentiation↗