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  • GENES  (2)
  • GENOME  (2)
  • 1
    Keywords: SPECTRA ; EXPRESSION ; IN-VITRO ; Germany ; VITRO ; GENE ; GENES ; PROTEIN ; PROTEINS ; PATIENT ; FAMILY ; SKIN ; SEQUENCE ; chromosome ; ACID ; IDENTIFICATION ; MUTATION ; MUTATIONS ; EPIDERMAL DIFFERENTIATION ; PHENOTYPE ; point mutation ; ARACHIDONIC-ACID ; EUROPE ; NOMENCLATURE ; CHROMOSOME 17P13.1 ; GENE-PRODUCT ; molecular ; ENZYME-ACTIVITIES ; ENZYME ; MISSENSE MUTATION ; MUTANTS ; recombinant protein ; SUBFAMILY ; ALOX12B ; ALOXE3 ; COLLODION BABY ; congenital ichthyosis ; genodermatosis ; genotype/phenotype correlation ; hepoxilin ; HEPOXILINS ; LAMELLAR ICHTHYOSIS ; lipoxygenase
    Abstract: Autosomal,recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often associated with erythema. To date, six loci for ARCI. have been mapped. Mutations in ALOXE3 and ALOX12B on chromosome 17p13, which code for two different epidermal lipoxygenases, were recently found in patients with ichthyosiform erythroderma from Turkey, France, and North Africa. Here we describe molecular and clinical findings in 17 families with ARCI originating from Central Europe, Turkey, and the Indian subcontinent, with mutations in ALOXE3 or ALOX12B. We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3. The gene products of ALOX12B and ALOXE3, the epidermal lipoxygenases 12R-LOX and eLOX3 respectively, are preferentially synthesized in the skin. They act in sequence to convert arachidonic acid via 12(R)-HPETE to the corresponding epoxyalcohol, 8(R)-hydroxy,11(R),12(R)-epoxyeicosatrienoic acid. To assess the impairment of enzyme activity, we expressed the mutated genes in vitro and determined the activity of the recombinant proteins toward their genuine substrates. All but one of the recombinant mutants were enzymatically inactive. The characterization of disease-causing mutations in ALOXE3 and ALOX12B and the resulting ARCI phenotypes did not result in clear diagnostic criteria; however, we found a first correlation between the genetic findings and the clinical presentation of ichthyosis
    Type of Publication: Journal article published
    PubMed ID: 16116617
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  • 2
    Keywords: DISEASE ; GENE ; GENOME ; MUTATIONS ; REGULATOR ; ALIGNMENT ; NUCLEAR FAMILIES ; SNP DATA ; CATARACT
    Abstract: Massively parallel ("next generation") DNA sequencing (NGS) has quickly become the method of choice for seeking pathogenic mutations in rare uncharacterized monogenic diseases. Typically, before DNA sequencing, protein-coding regions are enriched from patient genomic DNA, representing either the entire genome ("exome sequencing") or selected mapped candidate loci. Sequence variants, identified as differences between the patient's and the human genome reference sequences, are then filtered according to various quality parameters. Changes are screened against datasets of known polymorphisms, such as dbSNP and the 1000 Genomes Project, in the effort to narrow the list of candidate causative variants. An increasing number of commercial services now offer to both generate and align NGS data to a reference genome. This potentially allows small groups with limited computing infrastructure and informatics skills to utilize this technology. However, the capability to effectively filter and assess sequence variants is still an important bottleneck in the identification of deleterious sequence variants in both research and diagnostic settings. We have developed an approach to this problem comprising a user-friendly suite of programs that can interactively analyze, filter and screen data from enrichment-capture NGS data. These programs ("Agile Suite") are particularly suitable for small-scale gene discovery or for diagnostic analysis.
    Type of Publication: Journal article published
    PubMed ID: 23554237
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  • 3
    Keywords: CANCER ; CELL ; COMMON ; LUNG-CANCER ; DISEASE ; POPULATION ; RISK ; RISKS ; GENE ; GENES ; GENOME ; GENETIC POLYMORPHISMS ; cell cycle ; CELL-CYCLE ; CYCLE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; FREQUENCIES ; BREAST-CANCER ; genetics ; colorectal cancer ; COLORECTAL-CANCER ; CDKN2A ; ADENOCARCINOMAS ; TP53 ; RECTAL-CANCER ; VARIANT ; GENOTYPE ; HAPLOTYPES ; USA ; rectal cancer ; INCREASED RISK ; CANCERS ; Colorectal cancer susceptibility ; Haplotype analysis ; CRC ; CDKN1A ; P53 GENOTYPES ; WIDE ASSOCIATION SCAN
    Abstract: The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. To assess the role of genetic variants on the disease, we genotyped polymorphisms in the TP53 (rs17878362: A(1)〉A(2), rs1042522:G〉C, rs12947788: C〉T, and rs17884306:G〉A), CDKN1A (rs1801270: C〉A and rs1059234:C〉T), and CDKN2A (rs3731249:G〉A, rs11515:C〉G, and rs3088440: C〉T) genes in 614 hospital-based CRC cases and 614 matched controls from the country. Despite the tendency toward differential distribution of variant allele frequencies for some polymorphisms, none was significantly associated with CRC risk. We observed differential distribution of major haplotypes arising from four polymorphisms ill the TP53 gene between cases and controls (global P〈0.0001). The two most common haplotypes, A(1)GCG and A(2)CCG, were present in 81% of the cases compared to 71% of the controls. In comparison to the most common haplotype (A(1)GCG), the haplotype A2CCG was associated with an increased risk (odds ratio (OR], 1.40; 95% confidence interval [CI], 1.07-1.82), while the four other haplotypes A(1)CCG (OR, 0.60; 95% CI, 0.45-0.79), A(2)GCG (OR, 0.53; 95% CI, 0.35-0.81), A(1)GTG (OR, 0.31; 95% CI, 0.15-0.64), and A(1)GCA (OR, 0.19; 95% CI, 0.07-0.51) were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon (global P 〈 0.000 1) and rectal cancers (P = 0.006). No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. The results from this study suggest that prevalent haplotypes within the TP53 gene may modulate CRC risks in the population. Hum Mutat 30, 661-668, 2009. (C) 2009 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 19224585
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