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Marcel F Jonkman

Publications and source records attributed to Marcel F Jonkman.

22 records · Page 2Linked to original sources
PubMed2002

Partial revertant mosaicism of keratin 14 in a patient with recessive epidermolysis bullosa simplex.

A patient with recessive epidermolysis bullosa simplex due to a previously described homozygous KRT14 1842-2A-->C splice-site mutation was re-examined, because we unexpectedly found signs of revertant mosaicism. The germline mutation resulted in different aberrant transcripts containing premature termination codons, all leading to truncated keratin 14 proteins. Basal keratinocytes in skin and in culture completely lacked keratin 14 and intermediate filaments. From this keratin 14-/- patient we started cultures from a new skin biopsy and here, we serendipitously found keratinocytes that spontaneously expressed keratin 14. This biopsy had been taken from an area of skin that was clinically affected, because blisters could simply be evoked by gentle rubbing. Immunofluorescence and electron microscopy of additional biopsies from this skin area revealed a mosaic expression of keratin 14 and reappearance of intermediate filaments in basal keratinocytes. Immunoblotting showed a revertant keratin 14 polypeptide with seemingly normal molecular weight. DNA analysis of exon 2 and its flanking intron borders showed no additional mutations in the genomic KRT14 sequence. Analysis of mRNA isolated from mosaic skin keratinocytes revealed an additional in-frame transcript (1844T-->G, 1845Delta6) that codes for an abnormal keratin 14 polypeptide with a two residue deletion and one amino acid change. The re-expression of a revertant, albeit abnormal, keratin 14 polypeptide, so-called partial revertant mosaicism, accounts for the antibody staining pattern and for the reappearance of intermediate filaments, which however, are semifunctional and not able to revert the clinical phenotype. The combination of a keratin 14-positive and a keratin 14-negative cell population in epidermis as well as in cultured keratinocytes suggests that the cellular reversion might be caused by an endogenous factor. We hypothesize that a second somatic modulating factor in the genome that affects the processing of the mutant KRT14 pre-mRNA may underlie this phenomenon.

Aged↗
PubMed2002

Deletion of a cytoplasmic domain of integrin beta4 causes epidermolysis bullosa simplex.

Integrin alpha6beta4 is a hemidesmosomal transmembrane molecule involved in maintaining basal cell-matrix adhesion through interaction of the large intracytoplasmic tail of the beta4 subunit with the keratin intermediate filament network, at least in part through its binding with plectin and BP180/type XVII collagen. Here we report a patient with predominant features of epidermolysis bullosa simplex due to a mutation in the integrin beta4 gene. The patient, a 49-y-old female, had mild blistering of hands and feet from birth on, dystrophy of the nails with onychogryposis, and enamel hypoplasia. She had no alopecia and no history of pyloric atresia. Electron microscopy and antigen mapping of a skin blister revealed that the level of separation was intraepidermal, low in the basal keratinocytes through the attachment plaque of the hemidesmosome. Immuno-fluorescence microscopy revealed absent binding of monoclonal antibody 450-11 A against the third fibronectin III repeat on the intracellular domain of integrin beta4, whereas binding was reduced with monoclonal antibodies recognizing epitopes on amino-terminal and carboxy-terminal ends of the polypeptide. At the molecular level the phenotype was caused by a novel 2 bp deletion 4733delCT in ITGB4, resulting in in-frame skipping of exon 36 and a deduced 50 amino acid deletion (1450-1499) within the third fibronectin type III repeat in the cytoplasmic domain of the integrin beta4 polypeptide. Immunoblot analysis demonstrated a 5 kDa shorter beta4 polypeptide. The 4733delCT mutation was heterozygously present in the DNA. The patient is also expected to be heterozygous for a null allele, as no full-size protein was detected in vitro and the epitope 450-11 A was absent in vivo. These data show that deletion of the third fibronectin type III repeat in the cytoplasmic domain of integrin beta4, which is thought to interact with BP180/type XVII collagen, is clinically pathogenic and results in a mild phenotype with predominant features of epidermolysis bullosa simplex.

Base Sequence↗
PubMed2002

IgA-mediated epidermolysis bullosa acquisita: two cases and review of the literature.

We describe 2 adult patients with a subepidermal bullous dermatosis with exclusively linear IgA depositions along the epidermal basement membrane zone that were deposited in the sublamina densa zone as witnessed by direct immunoelectron microscopy. Indirect immunofluorescence microscopy of patients' sera revealed circulating IgA autoantibodies that bound exclusively to the dermal site of salt-split skin substrate. Immunoblot analysis using dermal and keratinocyte extracts were negative. Indirect immunofluorescence microscopy using type VII collagen-deficient skin ("knockout" substrate) showed no IgA binding, whereas linear IgA binding was seen at the epidermal basement membrane zone in normal human skin. The autoantigen in the patients was thus type VII collagen. A diagnosis of IgA-mediated epidermolysis bullosa acquisita (IgA-EBA) was made. We systematically reviewed the literature of this subset of patients with linear IgA dermatosis on the basis of the following criteria: exclusive binding of serum-IgA to the dermal side of salt-split skin or IgA depositions in the sublamina densa zone by indirect or direct immunoelectron microscopy. We learned that IgA-EBA is clinically indistinguishable from the classic "lamina-lucida type" linear IgA dermatosis or from the inflammatory type of IgG-mediated epidermolysis bullosa acquisita (IgG-EBA). Only a minority of the patients with IgA-EBA showed milia or scarring or had therapy-resistant ocular symptoms as in the mechanobullous type of IgG-EBA. Most patients with IgA-EBA responded to dapsone therapy.

Biopsy, Needle↗