Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A general improvement with ageing has been reported in a few cases of epidermolysis bullosa with pyloric atresia (PA-JEB), an autosomal recessive skin disease characterized by extensive disadhesion of epithelia. In a patient who improved from severe to mild PA-JEB, a search for mutations in the integrin beta4 gene (IGTB4) detected heterozygosity for a novel base substitution 3986-19T-->A in the putative branchpoint sequence of intron 31, and a point mutation 3802+1G-->A in the donor splice site of intron 30 previously associated with severe PA-JEB. Analysis of mRNA showed that the intronic mutation prevents legitimate splicing of the beta4 pre-mRNA. Functional splicing can be restored in vitro by seeding the proband's keratinocytes on feeders of irradiated fibroblasts. Study of mRNA in wild-type keratinocytes transfected with IGTB4 minigenes containing intron 31 with or without mutation 3986-19T-->A, confirmed the causative role of the intronic mutation in PA-JEB, and highlighted the influence of feeders on the maturation process of the mutated beta4 pre-mRNA. Our results show that in a context of overall reduction of the beta4 mRNA levels, activation of the legitimate splice site in the aberrant beta4 pre-mRNA underlies the transient severity of the condition. The results also point to the relevance which the interaction between epithelial and stromal cells may have in modulating expression of integrin receptors.
Hum Mol Genet 1999 Oct
PMID:Splicing modulation of integrin beta4 pre-mRNA carrying a branch point mutation underlies epidermolysis bullosa with pyloric atresia undergoing spontaneous amelioration with ageing. 1048 80

Epidermal keratinocytes are the primary target of the midrange ultraviolet part (UVB, 280-320 nm) of terrestrial sunlight. Analysis of the resulting UV response at the transcriptional level by differential display PCR identified a formerly unrecognized large group of repressed genes. Among those UV-repressible genes, a novel serine proteinase inhibitor (serpin) termed hurpin (HaCaT UV-repressible serpin) has been identified. The isolated full-length cDNAs harbour a 1176 bp open reading frame encoding a potential protein with 391 amino acid residues and a predicted molecular mass of approximately 44 kDa. The novel serpin has nearly 59 % amino acid identity with the squamous cell carcinoma antigen 1 (SCCA1) and squamous cell carcinoma antigen 2 (SCCA2). In addition, it displays all of the structural features unique to the ovalbumin family of serpins (ov-serpins). The amino acid sequence of the hinge region in the reactive site loop suggests that hurpin has the potential for protease inhibition. The putative reactive center P1-P1'residues were identified as Thr356-Ser357 by alignment with other ov-serpins. The physiological target protease is unknown and the in vitro translated hurpin does not form SDS-stable complexes with a variety of known serine proteases. Expression of hurpin is restricted to epidermal cells where two distinct transcripts of 3.0 and 3.4 kb are detectable. Furthermore, expression of hurpin appears to be related to the activation or proliferation state of keratinocytes, since hurpin transcripts are more abundant in immortalized keratinocytes (HaCaT) and in cultured normal human keratinocytes, compared to the expression in normal skin. Moreover, in psoriasis, a skin disease characterized by hyperproliferation of keratinocytes and responsive to therapeutic UV irradiation, overexpression of hurpin is noted in psoriatic skin lesions compared to non-lesional skin.
J Mol Biol 1999 Oct 15
PMID:Cloning and characterization of hurpin (protease inhibitor 13): A new skin-specific, UV-repressible serine proteinase inhibitor of the ovalbumin serpin family. 1051 13

Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Previous genetic linkage studies localized the gene to a 5 cM interval on human chromosome 3q21. After reducing the disease critical region to <1 cM, we used a positional cloning strategy to identify the gene ATP2C1, which is mutated in HHD. ATP2C1 encodes a new class of P-type Ca(2+)-transport ATPase, which is the homologue for the rat SPLA and the yeast PMR1 medial Golgi Ca(2+)pumps and is related to the sarco(endo)plasmic calcium ATPase (SERCA) and plasma membrane calcium ATPase (PCMA) families of Ca(2+)pumps. The predicted protein has the same apparent transmembrane organization and contains all of the conserved domains present in other P-type ATPases. ATP2C1 produces two alternative splice variants of approximately 4.5 kb encoding predicted proteins of 903 and 923 amino acids. We identified 13 different mutations, including nonsense, frameshift insertion and deletions, splice-site mutations, and non-conservative missense mutations. This study demonstrates that defects in ATP2C1 cause HHD and together with the recent identification of ATP2A2 as the defective gene in Darier's disease, provide further evidence of the critical role of Ca(2+)signaling in maintaining epidermal integrity.
Hum Mol Genet 2000 Apr 12
PMID:Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. 1076 38

A susceptibility gene for psoriasis, a chronic skin disorder, resides in chromosome 6p near the HLA-C locus. Sequencing of the region has allowed the identification of a new gene, HCR. We found that HCR is highly polymorphic with at least 12 coding variants. An association study of the new HCR polymorphisms and the previously suggested susceptibility alleles HLA-Cw*0602 and corneodesmosin allele 5 (CD*5) with psoriasis revealed a specific HCR variant associated with psoriasis susceptibility. However, the HLA-Cw*0602 allele was rarer in controls and associated with a stronger relative risk. Association analysis did not support CD*5 as a psoriasis susceptibility allele in our sample of patients (n = 100) and population-matched controls (n = 93) from an isolated population. We found HCR to be overexpressed in keratinocytes of psoriatic lesions compared with paired samples of healthy skin. Our results suggest a potential role for HCR in the pathogenesis of psoriasis.
Hum Mol Genet 2000 Jun 12
PMID:A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele. 1088 4

Psoriasis (PS) is a common skin disorder affecting approximately 2% of the Caucasian population. Despite the established influence of several environmental factors, epidemiological data and twin studies have long demonstrated a genetic basis for psoriasis susceptibility. Moreover an association between PS and HLA-Cw6 has been reported in different ethnic groups. In recent years, the availability of statistical methods for complex disease linkage analysis has prompted many researchers to carry out genome-wide scans. Their results have been conflicting and linkage replication has seldom been documented. However, a few chromosome regions have been confirmed in independent studies. In particular, compelling evidence supports the existence of a susceptibility locus within the HLA region. Moreover, loci on chromosomes 17q and 1q have been reported in at least two independent genome scans. Several groups have undertaken the refinement of regions identified during genome scans, using linkage disequilibrium data. This approach has allowed the fine mapping of the 6p21 locus, now restricted to a 60-kb genomic segment. As critical regions get smaller, candidate gene analysis becomes an attractive approach. So far, three genes have been extensively investigated: S100A7 on chromosome 1q and CDSN and HCR on chromosome 6p21. Even though several SNPs have been identified within these genes, none of them seems to meet the requirement needed to prove an involvement in PS pathogenesis. These criteria include association replication in different populations and functional studies of SNP biological significance. Thus, only a collaborative and multidisciplinary approach will allow the identification of PS susceptibility genes.
Mol Genet Metab
PMID:Advances in the search for psoriasis susceptibility genes. 1100 18

Bipolar affective disorder is a genetically complex psychiatric disorder with a population prevalence of approximately 1%. We have previously reported cosegregation of bipolar affective disorder and Darier's disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier's disease was mapped to chromosome 12q23-q24.1 and linkage studies by us and others have subsequently implicated this region as harbouring a susceptibility gene for bipolar affective disorder. In this study we have investigated the Darier's disease gene ATP2A2, the calcium pumping ATPase SERCA2, as a potential susceptibility gene for bipolar disorder under the hypothesis that variations in SERCA2 have pleiotropic effects in brain. Support for this hypothesis comes from clinical evidence of neuropsychiatric abnormalities in Darier's disease, genetic data produced in our study showing non-random clustering of missense mutations in ATP2A2 in neuropsychiatric Darier patients, and functional data demonstrating the role of SERCA2 in intracellular calcium regulation. In a panel of 15 unrelated bipolar patients from multiply affected families showing increased allele sharing at markers in the 12q23-q24.1 region, we performed mutational screening of the ATP2A2 coding sequence, promoter regions, and 3' untranslated region and identified six sequence variations. These were analysed in a large sample of bipolar patients (n = 324) and control subjects (n = 327). Analysis of allele and genotype distributions for all six variations, and of haplotype frequencies showed no evidence for the involvement of ATP2A2 in producing susceptibility to bipolar disorder.
Mol Psychiatry 2001 Jan
PMID:Exclusion of the Darier's disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder. 1124 92

Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities. We report the refinement of our previously described interval of MDM on chromosome 8qter, and the identification of mutations in affected individuals in the ARS (component B) gene, encoding a protein named SLURP-1, for secreted Ly-6/uPAR related protein 1. This protein is a member of the Ly-6/uPAR superfamily, in which most members have been localized in a cluster on chromosome 8q24.3. The amino acid composition of SLURP-1 is homologous to that of toxins such as frog cytotoxin and snake venom neurotoxins and cardiotoxins. Three different homozygous mutations (a deletion, a nonsense and a splice site mutation) were detected in 19 families of Algerian and Croatian origin, suggesting founder effects. Moreover, one of the common haplotypes presenting the same mutation was shared by families from both populations. Secreted and receptor proteins of the Ly-6/uPAR superfamily have been implicated in transmembrane signal transduction, cell activation and cell adhesion. This is the first instance of a secreted protein being involved in a PPK.
Hum Mol Genet 2001 Apr 01
PMID:Mutations in the gene encoding SLURP-1 in Mal de Meleda. 1128 53

In human patients, a wide range of mutations in keratin (K) 5 or K14 lead to the blistering skin disorder epidermolysis bullosa simplex. Given that K14 deficiency does not lead to the ablation of a basal cell cytoskeleton because of a compensatory role of K15, we have investigated the requirement for the keratin cytoskeleton in basal cells by inactivating the K5 gene in mice. We report that the K5(-/-) mice die shortly after birth, lack keratin filaments in the basal epidermis, and are more severely affected than K14(-/-) mice. In contrast to the K14(-/-) mice, we detected a strong induction of the wound-healing keratin K6 in the suprabasal epidermis of cytolyzed areas of postnatal K5(-/-) mice. In addition, K5 and K14 mice differed with respect to tongue lesions. Moreover, we show that in the absence of K5 and other type II keratins, residual K14 and K15 aggregated along hemidesmosomes, demonstrating that individual keratins without a partner are stable in vivo. Our data indicate that K5 may be the natural partner of K15 and K17. We suggest that K5 null mutations may be lethal in human epidermolysis bullosa simplex patients.
Mol Biol Cell 2001 Jun
PMID:Complete cytolysis and neonatal lethality in keratin 5 knockout mice reveal its fundamental role in skin integrity and in epidermolysis bullosa simplex. 1140 84

Approximately 2% of the Caucasian population is affected by psoriasis (PS); a chronic inflammatory skin disease triggered by both genetic and environmental risk factors. In addition to a major contribution from the HLA class I region, PS susceptibility loci have been mapped to a number of regions including 1q21, 3q21, 4qter, 14q31-q32, 17q24-q25, 19p13.3 and 20p. Some of these overlap with loci implicated in other autoimmune/inflammatory diseases. Global gene expression studies are beginning to provide insights into the etiology of these and other complex diseases. We used Affymetrix oligonucleotide arrays comprising approximately 12 000 known genes to initiate a more comprehensive analysis of the transcriptional changes that occur in involved and uninvolved skin of 15 psoriatic patients versus six normal controls. Expression levels of the transcripts detected on the arrays were first used to determine the relationship of samples to each other using hierarchical clustering. This analysis clearly differentiated involved psoriatic skin from uninvolved and normal skin. Clusters of differentially expressed genes with similar expression patterns in the same samples were then identified. Six out of 32 clusters contained a total of 177 transcripts that were differentially expressed in involved psoriatic skin versus normal skin. These differences were independent of the gender, age, skin site and HLA class I status of the patient. Ten of the 177 genes were also differentially expressed in uninvolved skin, and several mapped to regions previously shown to harbor psoriasis susceptibility loci.
Hum Mol Genet 2001 Aug 15
PMID:Insights into psoriasis and other inflammatory diseases from large-scale gene expression studies. 1153 89

An investigation was carried out on arsenic contamination of groundwater and prevalence of arsenical dermatosis in the Hetao plain of Inner Mongolia Autonomous Region, China. Based on the screening of water samples from 96 randomly selected wells in this Region, two areas (Wuyuan and Alashan) were chosen as highly contaminated areas because arsenic in the water samples was higher than 50 microg/l. Arsenic was measured using an arsenic silver diethyl dithiocarbamate method for 326 water samples from all the wells in these areas. The results show arsenic contaminated groundwater from tubule-type wells of depths about 15-30 m was serious compared with open-type wells where depth is about 3-5 m. In the Wuyuan area, 96.2% of water samples from tubule-type wells contained arsenic above 50 microg/l and 69.3% in Alashan area; the highest value was 1354 microg/l and 1088 microg/l, respectively. In these two areas, a health survey was carried out for arsenical dermatosis. The results show the prevalence of arsenical dermatosis in the Wuyuan area was 44.8%, higher than 37.1% prevalence of arsenical dermatosis in the Alashan area. The prevalence of arsenical dermatosis was highest in the over 40-year-old age group. There was no sex difference in the prevalence. Further investigation is needed to clarify the actual situation of arsenic pollution of groundwater in Inner Mongolia, China in order to reduce the adverse health effect among residents exposed to arsenic.
Mol Cell Biochem 2001 Jun
PMID:Arsenic contamination of groundwater and prevalence of arsenical dermatosis in the Hetao plain area, Inner Mongolia, China. 1167 95


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