Two cases of compositae dermatitis exacerbated by moisturizer containing feverfew.

A 45-year-old woman presented in October 2005 with a history of an eruption involving her scalp and face, including her eyelids and behind her ears. The eruption began at the end of August. It flared after she used a calming moisturizer containing feverfew (Tanacetum parthenium). A second patient, a 25-year-old woman, presented complaining of a 1-month history of an eruption around the eyes that started after she began using a moisturizer containing feverfew. Both patients were patch-tested with the North American Contact Dermatitis Group series, cosmetic and plant series, and their own skin care products. Patient 1 had a + reaction to sesquiterpene lactone mix, a + reaction to Compositae mix, a + reaction to parthenolide, a + reaction to Tanacetum vulgare, and a + reaction to the calming moisturizer. Patient 2 had + reactions to sesquiterpene lactone, Compositae mix, and the same calming moisturizer. It is thought that both of these eruptions are a result of contact dermatitis from the Compositae plant family.

Localized Darier's disease in a Blaschkoid distribution: two cases of phenotypic mosaicism and a review of mosaic Darier's disease.

Darier's disease is a rare autosomal dominant genodermatosis. Characteristic skin and nail changes consist of bilateral crusted red-brown papules and plaques in a seborrheic distribution, and V-shaped nicking or longitudinal ridging of the nails. In limited cases, a segmental distribution of this disease may be present in which localized lesions, found along the lines of Blaschko, are otherwise indistinguishable from those of generalized Darier's disease. Genomic mosaicism in localized lesions of Darier's disease is a new concept that was recently demonstrated in individuals of mosaic phenotypes. Both type 1 and type 2 mosaic phenotypes have been reported. We report two cases of type 1 localized Darier's disease in a Blaschkoid distribution and review the genetic implications of phenotypic mosaicism within the field of Darier's disease.

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

The receptor for activated C-kinase-I (RACK-I) anchors activated PKC-beta on melanosomes.

Protein kinase C (PKC), a family of at least eleven isoforms, mediates numerous cell functions. In human melanocytes, alpha, beta, delta, epsilon and zeta isoforms of PKC are expressed, but uniquely PKC-beta activates tyrosinase, the key and the rate-limiting enzyme in melanogenesis, by phosphorylating specific serine residues on its cytoplasmic domain. To investigate the mechanism by which only PKC-beta phosphorylates tyrosinase, we examined the expression of receptor for activated C-kinase-I (RACK-I), a receptor specific for activated PKC-beta, on the surface of melanosomes, the specialized organelle in which melanogenesis occurs. Immunoblot analysis of purified melanosomes revealed that RACK-I is readily detectable. Immunoprecipitation of RACK-I from purified melanosomes, followed by immunoblot analysis using antibody against PKC-beta, revealed abundant PKC-beta, whereas PKC-alpha was not detected when immunoblot analysis was performed using antibody against PKC-alpha. Activation of PKC in melanocytes increased the level of PKC-beta co-immunoprecipitated with RACK-I, while the level of melanosome-associated RACK-I decreased when melanocytes were treated chronically with the 12-0-tetradecanoyl-phorbol 13-Acetate (TPA), a condition known to deplete PKC and reduce tyrosinase activity. Immunoprecipitation with RACK-I antibody co-precipitated fewer PKC-beta in the presence of UV-activated 1, 1'-decamethylenebis-4-aminoquinaldinium di-iodide (DECA), known to disrupt the interaction between activated PKC-beta and RACK-I. Treatment of intact melanocytes with DECA also decreased tyrosinase activity. Moreover, suppression of RACK-I expression by transfecting melanocytes with siRNA against RACK-I reduced the basal tyrosinase activity and blocked TPA-induced increases in tyrosinase activity. Taken together, these results demonstrate that RACK-I anchors activated PKC-beta on the melanosome membrane, allowing PKC-beta to phosphorylate tyrosinase.

Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer.

Transfer of nucleic acid from cytoplasmic organelles to the nuclear genome is a well-established mechanism of evolutionary change in eukaryotes. Such transfers have occurred throughout evolution, but so far, none has been shown unequivocally to occur de novo to cause a heritable human disease. We have characterized a patient with a de novo nucleic acid transfer from the mitochondrial to the nuclear genome, a transfer that is responsible for a sporadic case of Pallister-Hall syndrome, a condition usually inherited in an autosomal dominant fashion. This mutation, a 72-bp insertion into exon 14 of the GLI3 gene, creates a premature stop codon and predicts a truncated protein product. Both the mechanism and the cause of the mitochondrial-nuclear transfer are unknown. Although the conception of this patient was temporally and geographically associated with high-level radioactive contamination following the Chernobyl accident, this case cannot, on its own, be used to establish a causal relationship between radiation exposure and this rare type of mutation. Thus, for the time being, it must be considered as an intriguing coincidence. Nevertheless, these data serve to demonstrate that de novo mitochondrial-nuclear transfer of nucleic acid is a novel mechanism of human inherited disease.