Reduced level of the repair/transcription factor TFIIH in trichothiodystrophy.
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Trichothiodystrophy (TTD) is a rare hereditary multisystem disorder associated with defects in nucleotide excision repair (NER) as a consequence of mutations in XPD, XPB or TTDA, three genes that are all related to TFIIH, the multiprotein complex involved in NER and transcription. Here we show that all the mutations found in TTD cases, irrespective of whether they are homozygotes, hemizygotes or compound heterozygotes, cause a substantial and specific reduction (by up to 70%) in the cellular concentration of TFIIH. Intriguingly, the degree of reduction in the level of TFIIH does not correlate with the severity of the pathological phenotype, suggesting that the severity of the clinical features in TTD cannot be related solely to the effects of mutations on the stability of TFIIH. We have also measured TFIIH levels in cells in which different mutations in the XPD gene are associated with clinical symptoms not of TTD but of the highly cancer-prone disorder xeroderma pigmentosum (XP). We have found mild reductions (up to 40%) in TFIIH content in some but not all of these cell strains. We conclude that the severity of the clinical features in TTD patients and the clinical outcome of differentially mutated XPD proteins is likely to depend both on the effects that each mutation has on the stability of TFIIH and on the transcriptional activity of the residual TFIIH complexes. (+info)
Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huet anomaly.
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The nature of the wild-type gene product at the mouse ichthyosis (ic) locus has been of great interest because mutations at this locus cause marked abnormalities in nuclear heterochromatin, similar to those observed in Pelger-Huet anomaly (PHA). We recently found that human PHA is caused by mutations in the gene (LBR) encoding lamin B receptor, an evolutionarily conserved inner nuclear membrane protein involved in nuclear assembly and chromatin binding. Mice homozygous for deleterious alleles at the ichthyosis (ic) locus present with a blood phenotype similar to PHA, and develop other phenotypic abnormalities, including alopecia, variable expression of syndactyly and hydrocephalus. The ic locus on mouse chromosome 1 shares conserved synteny with the chromosomal location of the human LBR locus on human chromosome 1. In this study, we identified one nonsense (815ins) and two frameshift mutations (1088insCC and 1884insGGAA) within the Lbr gene of mice homozygous for either of three independent mutations (ic, ic(J) and ic(4J), respectively) at the ichthyosis locus. These allelic mutations are predicted to result in truncated or severely impaired LBR protein. Our studies of mice homozygous for the ic(J) mutation revealed a complete loss of LBR protein as shown by immunofluorescence microscopy and immunoblotting. The findings provide the molecular basis for the heterochromatin clumping and other distinct phenotypes caused by ic mutations. These spontaneous Lbr mutations confirm the molecular basis of human PHA and provide a small animal model for determination of the precise function of LBR in normal and pathological states. (+info)
Self-healing collodion baby: a dynamic phenotype explained by a particular transglutaminase-1 mutation.
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Spontaneous healing with no or only very mild ichthyosis distinguishes the "self-healing collodion baby" from other congenital ichthyoses. In two self-healing collodion baby siblings with markedly diminished epidermal transglutaminase 1 activity we found the compound heterozygous transglutaminase 1 mutations G278R and D490G. Molecular modeling and biochemical assays of mutant proteins under elevated hydrostatic pressure suggest significantly reduced activity in G278R and a chelation of water molecules in D490G that locks the mutated enzyme in an inactive trans conformation in utero. After birth these water molecules are removed and the enzyme is predicted to isomerize back to a partially active cis form, explaining the dramatic improvement of this skin condition. (+info)
Dermatologic lesions in asymptomatic blood donors seropositive for human T cell lymphotropic virus type-1.
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Dermatologic manifestations are quite common in patients with adult T cell leukemia/lymphoma and myelopathy/tropical spastic paraparesis associated with infection with human T cell lymphotropic virus type-1 (HTLV-1). In this study, we evaluated the dermatologic lesions of eligible blood donors in the state of Minas Gerais in Brazil who were seropositive but asymptomatic for infection with HTLV-1. The study population was composed of 128 HTLV-1-seropositive individuals and 108 seronegative controls. All individuals underwent a dermatologic evaluation. Biopsy specimens were obtained from abnormal and normal skin samples of seropositive individuals in an attempt to detect HTLV-1 in tissue samples by a polymerase chain reaction. Dermatologic alterations were observed more frequently in the seropositive group (adjusted odds ratio [OR] = 8.77, 95% confidence interval [CI] = 4.11-18.71). The most common skin diseases were dermatophytoses (adjusted OR = 3.32, 95% CI = 1.50-7.35), seborrheic dermatitis (OR = 3.53, 95% CI = 0.67-24.66), and acquired ichthyosis (P = 0.001). Virus was detected more frequently in abnormal skin samples. Dermatologic lesions probably related to HTLV-1 infection were diagnosed in eligible blood donors who were infected with this virus, who were previously considered to be asymptomatic carriers of HTLV-1. (+info)
MENTAL RETARDATION: METHODS OF DIAGNOSIS AND SOME RECENTLY DESCRIBED SYNDROMES.
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Reduction of intelligence should be differentiated from interference with the use of intelligence by such non-intellective factors as partial deafness and emotional disturbance. The parents of a retarded child want an assessment, a prediction of the eventual achievement level, and a causal explanation if possible. There are varying degrees of knowledge of causation, from recognition of reduced intelligence only, to an understanding of the mechanism of causation in considerable detail from primary cause to ultimate consequence, as in phenylketonuria or isoimmunization. A diagnosis should be as complete as possible, using available modern techniques of investigation, such as chromatography and cytogenetic studies.AMONG THE RECENTLY DESCRIBED SYNDROMES ASSOCIATED WITH MENTAL RETARDATION ARE: (1) spastic paralysis and congenital ichthyosis; (2) Rud's syndrome; (3) deaf-mutism, infantilism, ataxia and a disturbance of hormone metabolism; and (5) sex-linked deaf-mutism. (+info)
Management of the ichthyoses.
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The ichthyoses are a heterogeneous group of inherited scaling skin disorders that can also affect other organs. Management should be directed at both the skin and other sites. Skin therapy is not specific at this time, although new products may offer more directed therapy in the future. Moisturizers and keratolytics are the mainstay of topical therapy. Calcipotriene, retinoids, and for select types, anti-inflammatories such as topical steroids and calcineurin inhibitors have also been used. Systemic therapy is limited to the retinoids. Superinfection of the skin should be anticipated and treated. Pruritus can be disabling. Failure to sweat normally may result in heat intolerance. Eye care should seek to prevent corneal changes resulting from ectropion and more specific changes associated with specific disorders. Haring can be impaired by the accumulation of material in the external auditory canal. Severely affected children may require caloric supplementation to avoid growth retardation. Affected individuals and their family should be counseled about the long term outlook and the genetic nature of their disorder, and informed of FIRST, the Foundation for Ichthyosis and Related Skin Types, the lay foundation that offers support and information. (+info)
Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1.
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Profilaggrin is a large epidermal polyprotein that is proteolytically processed during keratinocyte differentiation to release multiple filaggrin monomer units as well as a calcium-binding regulatory NH2-terminal filaggrin S-100 protein. We show that epidermal deficiency of the transmembrane serine protease Matriptase/MT-SP1 perturbs lipid matrix formation, cornified envelope morphogenesis, and stratum corneum desquamation. Surprisingly, proteomic analysis of Matriptase/MT-SP1-deficient epidermis revealed the selective loss of both proteolytically processed filaggrin monomer units and the NH2-terminal filaggrin S-100 regulatory protein. This was associated with a profound accumulation of profilaggrin and aberrant profilaggrin-processing products in the stratum corneum. The data identify keratinocyte Matriptase/MT-SP1 as an essential component of the profilaggrin-processing pathway and a key regulator of terminal epidermal differentiation. (+info)
Topical N-acetylcysteine treatment in neonatal ichthyosis.
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Unpredictable trancutaneous absorption of topically administered drugs and potential teratogenicity and toxicity of systemic drugs would make it mandatory to innovate more efficacious and less toxic drugs for the treatment of ichthyosis, which is not a fully curable disease in the neonatal period. In this article the clinical efficacy of 10% N-acetylcysteine emulsion in the topical treatment of congenital ichthyosis in a newborn was assessed, comparing simultaneously with 4% urea emulsion. After treating the skin of the left and right halves of the body with topical N-acetylcysteine and 4% urea, respectively, for nine days, the improvement was much more outstanding on the skin of the left half of the body when compared to the right half of the body. Topical N-acetylcysteine, to our knowledge, has not been used in a newborn with ichthyosis before, and this is the first report of a case of neonatal ichthyosis successfully treated with topical N-acetylcysteine. We conclude that 10% N-acetylcysteine emulsion, as an non-toxic and hypoallergic amino acid derivative, can be safely and efficaciously used in the topical treatment of neonatal ichthyosis, although the permanent cure may not always be possible. (+info)