Biomedical subjects
Publications and source records attributed to M F Jonkman.
Somatic reversion of inherited mutations is known for many years in plant breeding, however it was recognized only recently in humans. The concept of revertant mosaicism is important in medical genetics.
Studies of hereditary blistering skin diseases (epidermolysis bullosa) and targeted gene mutation experiments in knockout mice have greatly improved our understanding of hemidesmosomes and their associated structures in the cytoskeleton and basement membrane of the skin and mucous membranes. At least 10 molecules are recruited in hemidesmosome complexes, where they interact in a complex way. Hemidesmosomes are not simple adhesion devices, but also transduce signals for cell spreading, cell proliferation and basement membrane organisation. The dynamics of a hemidesmosome raises the metaphor of a self-assembling suspension bridge which evokes activities on both sides of the river. This review summarises our current knowledge of the molecular pathology of hemidesmosomes caused by hereditary skin disease or gene targeting experiment.
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A 13-year-old girl with severe non-mutilating recessive dystrophic epidermolysis bullosa (EB) was admitted to hospital because of a Staphyloccus aureussepsos, deterioration of her general condition and worsening of her skin disease, which itched severely. In addition to the blisters and erosions normally seen, she was covered from head to toe with scales and hyperkeratotic crusts. Despite intensive topical therapy, her skin condition did not improve significantly until scabies was detected and treated 1 week after admission. Because of the huge number of mites found and the crusted appearance, a diagnosis of crusted (Norwegian) scabies was made. She was successfully treated with two doses of ivermectin orally and one application of lindane ointment. Permethrin cream was not tolerated. In this patient crusted scabies may have developed because of: (i) a modified host response due to malnourishment; (ii) inability to scratch because of the absence of fingernails; and (iii) abnormal scratching behaviour because of the vulnerability of EB skin, or a combination of these factors. Limited isolation measures were taken on admission and full measures were taken immediately after the diagnosis of crusted scabies was made. Prophylactic treatment of ward personnel was not undertaken. Fortunately, there was not an outbreak of scabies in the hospital.
This study characterized the high molecular mass BP180 complex that is observed when unheated sodium dodecyl sulfate extracts of human skin or keratinocytes are subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. In heated extracts BP180 is present as a monomer with a molecular weight of 180 kDa, in unheated extracts BP180 runs at a molecular weight position over 500 kDa. By preincubating the unheated extracts at temperatures between 31 degrees C and 40 degrees C, the high molecular weight complex could be "melted" down to monomeric BP180. Under the conditions employed the T1/2 of the dissociation process was between 35 degrees C and 36 degrees C. The temperature resistance of the high molecular weight complex was used to analyze its molecular composition by performing two-dimensional electrophoresis with a "low-temperature" first dimension step and a "high-temperature" second dimension step. Silver staining and immunoblotting of the two-dimensional gels revealed the high molecular weight complex to be composed of solely BP180, indicating that the complex is the nondissociated homotrimeric form of BP180. The 120 kDa linear IgA dermatosis antigen (LAD-1) is an collagenous anchoring filament protein with homology to the extracellular collagenous part of BP180. Two-dimensional immunoblotting showed that LAD-1, as BP180, is also present as a high molecular mass complex and does not form mixed complexes with BP180.
A 12 y old girl with the albopapuloid variant (Pasini) of dominant dystrophic epidermolysis bullosa is studied. The albopapuloid lesions developed within the first year of life, contained milia and were associated with pruritus. Mutation detection of the COL7A1 gene revealed a G-->A transition at nucleotide position 6110 in the mutant allele converting a glycine to glutamic acid (G2037E). This report adds to the expanding database on COL7A1 mutations in dystrophic epidermolysis bullosa.
Pharmacokinetics of intravenous and oral pulsed high-dose dexamethasone were studied in four patients with pemphigus vulgaris. Doses for dexamethasone were varied from 100 to 300 mg. Serum concentrations were measured by high-performance liquid chromatographic procedure with diode assay detection. Bioavailability was assessed by comparing the areas under the serum concentration-time curves following oral administration with those of intravenous administration. Mean bioavailability of high-dose oral dexamethasone was 63.4%. Side effects were minor and were limited to temporary facial flushing both after oral and intravenous administration. Oral administration of dexamethasone in pemphigus patients showed to be more convenient and cost effective than administration by the intravenous route.
Epidermolysis Bullosa is characterised by blister formation of skin and mucous membranes. Three major varieties of epidermolysis bullosa (EB) are reviewed including their dental and oral aspects: EB simplex, junctional EB and dystrophic EB. Marked oral involvement of the soft and hard tissues can produce potentially devastating alterations in anatomy and function. Oral debilitation is limited primarily to the recessive dystrophic EB type due to soft tissue scarring following blister formation. Microstomia, ankyloglossia and obliteration of the oral vestibule are typical features of dystrophic EB. In other cases enamel hypoplasia and cementum disorders can be present. Epidermolysis bullosa has considerable impact on oral health and dental care.
In a 48-year-old man who suffered from progressive loss of vision in his left eye and metamorphopsia, pseudoxanthoma elasticum was diagnosed. Angioid streaks were observed in both eyes and the skin showed small yellow papules in a linear pattern. The right retina was twice treated by laser coagulation which resulted in temporary regression of neovascularization. Pseudoxanthoma elasticum is a genetic disorder with variable penetrance. There is no treatment. Patients should be told to refrain from contact sports and to avoid using aspirin.
A patient is described who initially presented with an acrovesicular eczema which subsequently developed into erythema multiforme with histopathological features of bullous pemphigoid. Although the various laboratory studies pointed to the diagnosis of paraneoplastic pemphigus (PNP), the underlying neoplasm was not detected until 6 months later, when the biopsies of an oral lesion showed the presence of an underlying non-Hodgkin lymphoma.
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Pachyonychia congenita type 2 (PC-2; Jackson-Lawler syndrome) is an autosomal dominant disorder characterized by hypertrophic nail dystrophy, mild focal keratoderma, multiple pilosebaceous cysts and other features of ectodermal dysplasia. Keratin 17 (K17) is a differentiation-specific keratin expressed in the nail bed, hair follicle, sebaceous gland and other epidermal appendages. Previously, we have demonstrated that PC-2 is caused by mutations in K17 and that similar mutations in this gene can present as steatocystoma multiplex with little or no nail dystrophy. Here, we describe three unrelated kindreds carrying K17 mutations. Two of these families have identical missense mutations (R94C) in the 1A domain of K17. However, while affected members of one kindred have the classical features of PC-2, affected persons in the other family have the steatocystoma multiplex phenotype. In a third family with PC-2, mutation N92S was detected, bringing the total number of distinct mutations reported in K17 thus far to 11. These results demonstrate that K17 mutations commonly underlie both PC-2 and steatocystoma multiplex and that the alternate phenotypes which arise from these genetic lesions in K17 are independent of the specific mutation involved.
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.
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Type I and type II keratins form the heteropolymeric intermediate filament cytoskeleton, which is the main stress-bearing structure within epithelial cells. Pachyonychia congenita (PC) is a group of autosomal dominant disorders whose most prominent phenotype is hypertrophic nail dystrophy accompanied by other features of ectodermal dysplasia. It has been shown previously that mutations in either K16 or K6a, which form a keratin expression pair, produce the PC-1 variant (MIM 184510). Mutations in K17 alone, an unpaired accessory keratin, result in the PC-2 phenotype (MIM 184500). Here, we describe a family with PC-2 in which the K17 locus on 17q was excluded and linkage to the type II keratin locus on 12q was obtained (Z max 3.31 at straight theta = 0). Mutation analysis of candidate keratins revealed the first reported missense mutation in K6b, implying that this keratin is the previously unknown expression partner of K17, analogous to the K6a/K16 pair. Co-expression of these genes was confirmed by in situ hybridization and immunohistochemical staining. These results reveal the hitherto unknown role of the K6b isoform in epithelial biology, as well as genetic heterogeneity in PC-2.
A case is presented of subepidermal, autoimmune bullous disease in which the initial examinations suggested the combination of epidermolysis bullosa acquisita and bullous pemphigoid. The diagnosis of epidermolysis bullosa acquisita was made by indirect immunofluorescence microscopy: the patient's serum bound to normal skin substrate but not to type VII collagen-deficient skin substrate derived from a patient with mutilating dystrophic epidermolysis bullosa. The use of skin substrates deficient in basement membrane molecules also excluded the presence of concomitant, circulating bullous pemphigoid autoantibodies in our patient. The diagnosis of epidermolysis bullosa acquisita was confirmed by split mapping, fluorescence overlay antigen mapping and Western blot.
Generalized atrophic benign epidermolysis bullosa (GABEB; OMIM no. 226650) is a rare hemidesmosomal variant of EB, inherited in an autosomal recessive fashion. In previous studies, mutations in the gene (COL17A1) encoding the type XVII collagen, a transmembrane component of hemidesmosomes, were detected in most patients with GABEB. However, evidence for genetic defects in the laminin 5 genes has also been presented. In the present investigation, we examined three patients, representing two families with GABEB, for mutations in the LAMB3 gene. Heteroduplex scanning of the gene, followed by direct automated sequencing, revealed that Patient 1 was a compound heterozygote for a missense mutation (C293S) and a premature termination codon-causing mutation (1367delAC). The latter mutation resulted in accelerated mRNA decay, which rendered the corresponding mRNA transcript undetectable by reverse transcriptase-PCR. Patients 2 and 3, siblings with slightly different clinical presentations, were homozygous for a G-->A transition affecting the last nucleotide of exon 7 (628G-->A). This mutation resulted in amino acid substitution (E210K), as well as in multiple aberrant splice variants affecting exons 6 to 8. These observations expand the repertoire of LAMB3 mutations in nonlethal variants of EB, and they illustrate the consequences of the mutations at the mRNA and protein levels.
Mitotic gene conversion acting as reverse mutation has not been previously demonstrated in human. We report here that the revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene conversion of one of the two mutated COL17A1 alleles. Specifically, the maternal allele surrounding the mutation site on COL17A1 (1706delA) showed reversion of the mutation and loss of heterozygosity along a tract of at least 381 bp in revertant keratinocytes derived from clinically unaffected skin patches; the paternal mutation (R1226X) remained present in all cell samples. Revertant mosaicism represents a way of natural gene therapy.