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PubMed1996

Clinicopathological correlations of compound heterozygous COL7A1 mutations in recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa is an inherited mechano-bullous disorder of skin and mucous membranes. Ultrastructurally, the disease is characterized by abnormalities of anchoring fibrils, attachment structures below the epidermal basement membrane, composed of type VII collagen. Mutations in the type VII collagen gene (COL7A1) have been shown conclusively to underlie dystrophic epidermolysis bullosa. Since there is variation of the phenotype, accompanied by heterogeneous anchoring fibril morphology and type VII collagen immunostaining, it is conceivable that different types and combinations of COL7A1 mutations correlate with different phenotypes. We therefore screened recessive dystrophic epidermolysis bullosa patients for COL7A1 mutations. Three unrelated patients showed the same premature termination codon mutation in exon 13 of one allele, yet they were all compound heterozygotes, each having a different mutation in the second allele. The first patient had a premature termination codon within the collagenous region of COL7A1 associated with severe disease, absent anchoring fibrils and undetectable type VII collagen immunostaining. The second had a premature termination codon in the non-collagenous NC-2 region associated with severe disease, wispy anchoring fibrils, and patchy type VII collagen immunostaining. The third had a glycine-to-aspartic acid substitution within the collagenous region, associated with milder disease, no identifiable anchoring fibrils, but near normal type VII collagen immunostaining. We conclude that the nature and position of mutations within COL7A1 correlate with specific disease features and may provide an insight into the molecular mechanisms of anchoring fibril formation and epidermal-dermal adhesion.

Adult↗
PubMed1996

Molecular basis of recessive dystrophic epidermolysis bullosa: genotype/phenotype correlation in a case of moderate clinical severity.

Mutations within the gene encoding the anchoring fibril protein type VII collagen (COL7A1) have recently been established as the pathogenetic basis for the inherited blistering skin disorder, dystrophic epidermolysis bullosa. We report a patient with a moderately severe phenotype of recessive dystrophic epidermolysis bullosa. We report a patient with a moderately severe phenotype of recessive dystrophic epidermolysis bullosa, in whom COL7A1 mutations have been identified on both alleles. The patient is a 5-y-old Japanese male of nonconsanguineous parents, with clinical features including generalized trauma-induced blistering since birth, complete loss of nails, and partial fusion of the fingers and toes. Immunofluorescence microscopy examination of the dermal-epidermal junction in the patient's skin revealed near-normal intensity staining with an antitype VII collagen antibody (LH7:2). Transmission electron microscopy showed a reduced number of thin, poorly-formed anchoring fibrils. PCR amplification of genomic DNA, followed by heteroduplex analysis, and nucleotide sequencing demonstrated that the patient was a compound heterozygote for a nonsense mutation (E2858X) within the NC-2 domain of type VII collagen and a missense mutation (G2576R) within the type VII collagen triple helix. Both mutations were verified by restriction endonuclease digestion. Information about these mutations advances our understanding of genotype-phenotype correlations in dystrophic epidermolysis bullosa, and further delineates the mechanisms involved in dermal-epidermal dysadhesion.

Base Sequence↗
PubMed1993

Normal molecular weight of type VII collagen produced by recessive dystrophic epidermolysis bullosa keratinocytes.

Studies of the recessive dystrophic form of epidermolysis bullosa (RDEB) have suggested that an abnormality in type VII collagen may be involved in the pathogenesis of this disorder. Indirect immunofluorescence studies have shown that the staining for type VII collagen along the dermal-epidermal junction is markedly reduced or absent in all but rare cases of severe, generalized RDEB. These findings imply that the genetic defect may involve type VII collagen but do not exclude the possibility that the alterations demonstrated are secondary, for example, to nonspecific proteolysis of type VII collagen. To evaluate the ability of cells of affected patients to produce type VII collagen, we cultured keratinocytes from a severely affected patient and immunoprecipitated type VII collagen from the cells. Keratinocytes were metabolically labelled with 35S-methionine, and solubilized cell extracts were reacted with antibody to type VII collagen. The results indicate that the patient's keratinocytes synthesize type VII collagen and that the M(r) of the protein synthesized does not differ from that of an unaffected control. Because cultured cells from a patient severely affected with recessive dystrophic epidermolysis bullosa produce type VII collagen, the genetic defect, at least in this patient, is unlikely to reside in a major truncation of the type VII collagen molecule.

Collagen↗
PubMed1994

Collagen VII in severe recessive dystrophic epidermolysis bullosa: expression of mRNA but lack of intact protein product in skin and cutaneous cells in vitro.

The collagen VII gene, COL7A1, is the candidate gene for both the recessive and dominant forms of dystrophic epidermolysis bullosa (EBD). Collagen VII is a structural protein of the anchoring fibrils, which are rudimentary or altered in several subtypes of EBD. In severe recessive mutilating EBD, anchoring fibrils and collagen VII are not detectable in skin of most patients. To elucidate the underlying pathogenetic mechanisms, we analyzed collagen VII expression in cutaneous cells of six patients with this severe EBD subtype. Neither keratinocytes nor fibroblasts synthesized detectable amounts of collagen VII protein; however, Northern blot analysis revealed small amounts of normal-size collagen VII mRNA in both EBD and control fibroblasts. When the mRNA was amplified using reverse transcription-polymerase chain reaction, correct amplimers were present in all specimens. The results demonstrate that transcription of the COL7A1 gene occurs in these patients with severe mutilating EBD and suggest that post-transcriptional or post-translational events lead to absence of collagen VII protein from skin.

Adult↗
PubMed1991

Animal model for dermolytic mechanobullous disease: sheep with recessive dystrophic epidermolysis bullosa lack collagen VII.

A severe congenital mechanobullous disease with dermolytic blistering and recessive inheritance is described in sheep. The affected animals of wild and inbred flocks of the breed Weisses Alpenschaf (WAS) have blisters of skin, oral mucosa, tongue, and esophagus at birth or within the first week of life. Exungulation occurs early, and severe erosions in the mouth lead to difficulty in feeding. Electron microscopic examination revealed sub-lamina densa splitting in natural or fresh friction blisters and absence of identifiable anchoring fibrils in clinically uninvolved skin. Antigen mapping localized laminin and collagen IV to the blister roof. Indirect immunofluorescence staining with antibodies to collagen VII, the major structural component of the anchoring fibrils, demonstrated a complete absence of reaction in clinically uninvolved tissues of the affected sheep, whereas in normal sheep a strong linear fluorescence was seen at the epithelial-mesenchymal basement membrane zone. Dermal extracts of normal sheep contained intact collagen VII, but epidermal and dermal extracts from the affected sheep lacked this collagen or its fragments in immunoblotting experiments. Based on genetic, clinical, ultrastructural, and immunochemical findings, the sheep disorder corresponds to the severe mutilating subtype of recessive dystrophic epidermolysis bullosa in humans and can be used as an animal model to investigate the human disorder.

Animals↗
PubMed1989

The carboxyl-terminal domain of type VII collagen is present at the basement membrane in recessive dystrophic epidermolysis bullosa.

Recent studies showing that type VII collagen is a component of anchoring fibrils suggests that the absence of anchoring fibrils in recessive dystrophic epidermolysis bullosa may be due to a defect in the synthesis, secretion, and deposition of type VII collagen. That hypothesis is further supported by recent studies suggesting that monoclonal antibodies to type VII collagen do not react with the basement membrane in most patients. To investigate further, we examined skin from 12 patients by electron microscopy and by immunohistology and immunoelectron microscopy using a concentrated and purified monoclonal antibody to the carboxy-terminal domain of Type VII collagen. Although anchoring fibrils were not detected by electron microscopy, the results of immunohistology showed definite, but reduced, binding of the monoclonal antibody to type VII collagen at the basement membrane in a linear pattern in 11 of 12 patients. By immunoelectron microscopy, reduced deposition of anti-type VII collagen antibody was detected beneath the lamina densa. The results of this study show that the carboxyl-terminal domain of type VII collagen is synthesized, secreted, and deposited at the basement membrane zone in 11 of 12 patients with recessive dystrophic epidermolysis bullosa and suggest that the absence of anchoring fibrils may be due either to deposition of abnormal type VII collagen, reduced levels of normal type VII collagen, defective assembly of type VII collagen into anchoring fibrils, or destruction of the collagenous domain of type VII collagen.

Antibodies, Monoclonal↗
PubMed2004

Involvement of p53 and p16 tumor suppressor genes in recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma.

Recessive dystrophic epidermolysis bullosa (RDEB) is an autosomal recessive disorder characterized by the loss of collagen type VII, an intrinsic component of the anchoring fibrils, which attach the epidermis to the dermis. Of the genetic blistering disorders, RDEB has the highest rate of morbidity and mortality, with morbidity arising from fusion of digits in a mitten-glove deformity and growth retardation associated with anemia. The leading cause of death in RDEB is cutaneous squamous cell carcinoma, which causes death through invasion and metastasis. In order to better understand the pathogenesis of these rare but aggressive squamous cell carcinoma (SCC), we analyzed them for mutations in p53 and loss of p16ink4a. Three tumors demonstrated mutations in the p53 tumor suppressor gene. We also analyzed SCC from patients with RDEB for the presence of p16ink4a hypermethylation, and found two tumors that have loss of p16ink4a through hypermethylation. This is the first description of specific abnormalities in tumor suppressor genes in RDEB associated SCC, and demonstrates that alterations in both p53 and p16ink4a can contribute to RDEB associated SCC.

Carcinoma, Squamous Cell↗
PubMed2005

Desmoglein 4 mutations underlie localized autosomal recessive hypotrichosis in humans, mice, and rats.

A newly defined form of inherited hair loss, named localized autosomal recessive hypotrichosis (LAH, OMIM 607903), was recently described in the literature and shown to be linked to chromosome 18. A large, intragenic deletion in the desmoglein 4 gene (DSG4) as the underlying mutation in several unrelated families of Pakistani origin. LAH is an autosomal recessive form of hypotrichosis affecting the scalp, trunk, and extremities, and largely sparing the facial, pubic, and axillary hair. Typical hairs are fragile and break easily, leaving short sparse scalp hairs with a characteristic appearance. Using comparative genomics, we also demonstrated that human LAH is allelic with the lanceolate hair (lah) mouse, as well as the lanceolate hair (lah) rat phenotype. Together, these models provide new information about the role of desmosomal cadherins in disease, and serve as in vivo models for functional and mechanistic studies into the role of desmoglein 4 in the skin and hair follicle.

Animals↗
PubMed1994

Autosomal recessive epidermolysis bullosa simplex. A case report.

We report a male child with autosomal recessive epidermolysis bullosa simplex presenting at birth. The patient subsequently developed cutaneous atrophy, nail dystrophy, milia and alopecia. He had growth retardation and anaemia, but there were no other associated abnormalities. Electron microscopy showed epidermolytic cleavage. The family history indicated an autosomal recessive mode of inheritance.

Consanguinity↗
PubMed1994

Clinical, light and electron microscopic features of recessive congenital ichthyosis type I.

Based on electron microscopic features, recessive congenital ichthyoses have recently been divided into four subgroups designated ichthyosis congenita (IC) types I, II, III and IV. Type II is characterized by cholesterol clefts in the horny cells, type III by perinuclear elongated membranes in the granular and horny cells, and type IV by masses of lipid membranes in granular and horny cells. Clear electron microscopic criteria for type I are lacking, although the presence of lipid droplets in the horny cells has been suggested as a criterion. In the present study we included ichthyosis patients with (i) recessive inheritance, (ii) erythrodermic fine scaling, (iii) lack of fine structural markers of IC types II-IV. Patients with ichthyotic syndromes were excluded. The case material consisted of 21 patients from 14 families. Eight were collodion babies at birth, but three were normal. Nine had ectropion, the flexures were affected in 12, and the palms and soles were thickened in all but one patient. On electron microscopy lipid vacuoles in the horny cells were common, but were absent in four patients. Changes in other lipid-related structures, including keratinosomes, were common. We conclude that currently type I can be diagnosed only by excluding the other types of ichthyosis. Clinically, IC type I corresponds to classical non-bullous congenital ichthyosiform erythroderma, but there is marked heterogeneity among affected individuals.

Adolescent↗
PubMed2005

Mild recessive epidermolytic hyperkeratosis associated with a novel keratin 10 donor splice-site mutation in a family of Norfolk terrier dogs.

BACKGROUND: Epidermolytic hyperkeratosis in humans is caused by dominant-negative mutations in suprabasal epidermal keratins 1 and 10. However, spontaneous keratin mutations have not been confirmed in a species other than human. OBJECTIVES: To describe an autosomal recessive, mild, nonpalmar/plantar epidermolytic ichthyosis segregating in an extended pedigree of Norfolk terrier dogs due to a splice-site mutation in the gene encoding keratin 10 (KRT10). METHODS: Dogs were evaluated clinically, and skin samples were examined by light and electron microscopy. Genomic DNA samples and cDNA from skin RNA were sequenced and defined a mutation in KRT10. Consequences of the mutation were evaluated by assessing protein expression with immunohistochemistry and Western blotting and gene expression with real-time RT-PCR (reverse transcriptase-polymerase chain reaction). RESULTS: Adult dogs with the disease had generalized, pigmented hyperkeratosis with epidermal fragility. Light microscopic examination defined epidermolysis with hyperkeratosis; ultrastructural changes included a decrease in tonofilaments and abnormal filament aggregation in upper spinous and granular layer keratinocytes. Affected dogs were homozygous for a single base GT-->TT change in the consensus donor splice site of intron 5 in KRT10. Keratin 10 protein was not detected with immunoblotting in affected dogs. Heterozygous dogs were normal based on clinical and histological appearance and keratin 10 protein expression. The mutation caused activation of at least three cryptic or alternative splice sites. Use of the cryptic sites resulted in transcripts containing premature termination codons. One transcript could result in shortening of the proximal portion of the 2B domain before the stutter region. Quantitative real-time PCR indicated a significant decrease in KRT10 mRNA levels in affected dogs compared with wild-type dogs. CONCLUSIONS: This disease is the first confirmed spontaneous keratin mutation in a nonhuman species and is the first reported recessive form of epidermolytic hyperkeratosis.

Animals↗
PubMed2004

The potyvirus recessive resistance gene, sbm1, identifies a novel role for translation initiation factor eIF4E in cell-to-cell trafficking.

From the characterization of the recessive resistance gene, sbm1, in pea we have identified the eukaryotic translation initiation factor, eIF4E, as a susceptibility factor required for infection with the Potyvirus, Pea seed-borne mosaic virus. A functional analysis of the mode of action of the product of the dominant allele revealed a novel function for eIF4E in its support for virus movement from cell-to-cell, in addition to its probable support for viral RNA translation, and hence replication. Different resistance specificities in two independent pea lines were explained by different mutations in eIF4E. On the modelled structure of eIF4E the coding changes were in both cases lying in and around the structural pocket involved in binding the 5'-m7G cap of eukaryotic mRNAs. Protein expression and cap-binding analysis showed that eIF4E encoded by a resistant plant could not bind to m7G-Sepharose, a result which may point to functional redundancy between eIF4E and the paralogous eIF(iso)4E in resistant peas. These observations, together with related findings for other potyvirus recessive resistances, provide a more complete picture of the potyvirus life cycle.

Alleles↗
PubMed1992

Recessive dystrophic epidermolysis bullosa treated with phenytoin.

Three patients with severe recessive dystrophic epidermolysis bullosa were treated with oral phenytoin and palliative and supportive measures for variable periods. Their progress was compared with that of three milder cases managed only with palliative and supportive measures. The phenytoin-treated group showed marked decrease in blister count, increase in trauma tolerance, a rise in hemoglobin level, and considerable weight gain. The results support earlier reports that collagenase inhibitors are useful in controlling blister formation in recessive dystrophic epidermolysis bullosa.

Administration, Oral↗
PubMed1978

Ichthyosis vulgaris showing features of the autosomal dominant and X-linked recessive variants in the same family.

A family in which the mother and six of her sons present an ichthyosis of the vulgaris type has been analysed clinically, histologically and electron microscopically. Phenotypically the ichthyosis in the mother is purely of the dominant type, while that in all the affected sons shows, to varying degrees, features of both the dominant and X-linked recessive variants. The findings are interpreted as reasonably good evidence that the mother has transmitted to all her affected sons both the autosomal dominant and the X-linked recessive genes for ichthyosis. Although genetically this is a most unusual situation, it corresponds best to our findings.

Adolescent↗
PubMed1978

Autosomal recessive inheritance of metaphyseal dysplasia (Pyle disease).

Two young adults with Pyle disease have been investigated in a large Afrikaner kindred in South Africa. Consanguinity was present in the family, and it is likely that the condition was inherited as an autosomal recessive. This contention is supported by the radiographic demonstration of minor degrees of widening of the distal femora in obligatory and potentially heterozygous relatives. Apart from genu valgus of moderate degree, the patients enjoyed good health and their gross radiographic skeletal abnormalities contrasted with the innocuous clinical presentation. Differentiation of Pyle disease from the autosomal dominant and autosomal recessive forms of cranio-metaphyseal dysplasia is of prognostic importance in view of the potentially serious complications in these latter disorders.

Adult↗
PubMed1986

Discoid lupus erythematosus-like skin lesions in a patient with autosomal recessive chronic granulomatous disease.

A case of chronic granulomatous disease (CGD) in a 32-year-old female with two episodes of opportunistic infections is described. At the age of 29 the patient was suspected to be a carrier of X-linked CGD on the basis of discoid lupus erythematosus-like skin lesions. No respiratory burst activity, as measured by phorbol myristate acetate stimulated superoxide production, was observed in isolated neutrophils of the patient. Membrane-rich fractions elicited no superoxide production in the presence of NADPH. The neutrophil content of cytochrome b-245 was within normal range. Family investigations revealed neither cellular abnormalities nor any history of skin diseases or opportunistic infections in first degree relatives. The parents of the patient were first cousins. On the basis of family history and the in-vitro assessment of neutrophil function, the patient is believed to have autosomal recessive CGD. The presented case illustrates that lupus erythematosus-like skin lesions are not restricted to female carriers of X-linked CGD, but may also be found in the autosomal recessive type of the disease.

Adult↗
PubMed1987

Autosomal recessive inheritance of idiopathic dilated cardiomyopathy in a Madeira Portuguese kindred.

Cardiomyopathy is a heterogeneous disorder with numerous inherited and acquired causes. Familial, isolated, dilated cardiomyopathy is usually reported as being inherited in an autosomal dominant mode with variable penetrance and expressivity. In this paper we describe a form of autosomal recessively inherited, dilated, cardiomyopathy occurring in three members of a consanguineous Madeira Portuguese family. Following review of the literature, it appears that the autosomal recessive form of dilated cardiomyopathy is more common than previously reported.

Adult↗
PubMed1988

Familial congenital fiber type disproportion (CFTD) with an autosomal recessive inheritance.

Two siblings, born to healthy non-consanguineous parents, were found to be affected with congenital progressive severe myopathy. Muscle biopsy revealed fiber type disproportion with no other histological abnormalities, thus confirming the diagnosis of congenital fiber type disproportion and suggesting an autosomal recessive mode of inheritance. This, to our knowledge, is the first reported family in which a strict histological diagnosis of congenital fiber type disproportion has been made and an autosomal recessive mode of inheritance shown.

Child↗