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  • 1
    Abstract: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of monogenic genodermatoses that encompasses non-syndromic disorders of keratinization. The pathophysiology of ARCI has been linked to a disturbance in epidermal lipid metabolism that impaired the stratum corneum function, leading to permeability barrier defects. Functional characterization of some genes involved in ARCI contributed to the identification of molecular actors involved in epidermal lipid synthesis, transport or processing. Recently, PNPLA1 has been identified as a gene causing ARCI. While other members of PNPLA family are key elements in lipid metabolism, the function of PNPLA1 remained unclear. We identified 5 novel PNPLA1 mutations in ARCI patients, mainly localized in the putative active enzymatic domain of PNPLA1. To investigate Pnpla1 biological role, we analysed Pnpla1-deficient mice. KO mice died soon after birth from severe epidermal permeability defects. Pnpla1-deficient skin presented an important impairment in the composition and organization of the epidermal lipids. Quantification of epidermal ceramide species highlighted a blockade in the production of omega-O-acylceramides with a concomitant accumulation of their precursors in the KO. The virtually loss of omega-O-acylceramides in the stratum corneum was linked to a defective lipid coverage of the resistant pericellular shell encapsulating corneocytes, the so-called cornified envelope, and most probably disorganized the extracellular lipid matrix. Finally, these defects in omega-O-acylceramides synthesis and cornified envelope formation were also evidenced in the stratum corneum from PNPLA1-mutated patients. Overall, our data support that PNPLA1/Pnpla1 is a key player in the formation of omega-O-acylceramide, a crucial process for the epidermal permeability barrier function.
    Type of Publication: Journal article published
    PubMed ID: 28369476
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  • 2
    Keywords: CELLS ; CELL ; Germany ; DISTINCT ; ENZYMES ; GENE ; GENES ; PROTEINS ; RNA ; transcription ; ACTIVATION ; COMPLEX ; COMPLEXES ; DNA ; MECHANISM ; mechanisms ; BIOLOGY ; MOLECULAR-BIOLOGY ; CHROMATIN ; genetics ; INTERACTS ; CHROMATIN STRUCTURE ; METHYLATION ; heredity ; LAYER ; molecular biology ; molecular ; MOLECULAR-MECHANISM ; review ; RE ; LIFE ; POLYMERASE-I TRANSCRIPTION ; MOLECULAR-MECHANISMS ; ENZYME ; METHYLTRANSFERASES ; NoRC ; NUCLEOLAR DOMINANCE ; GROWTH-CONTROL
    Abstract: Eukaryotic cells contain several hundred ribosomal RNA (rRNA) genes (rDNA), a fraction of them being silenced by epigenetic mechanisms. The presence of two epigenetically distinct states of rRNA genes provides a unique opportunity to decipher the molecular mechanisms that establish the euchromatic, i.e. transcriptionally active, and the heterochromatic, i.e. transcriptionally silent, state of rDNA. This article summarizes our knowledge of the epigenetic mechanisms that control rDNA transcription and emphasizes how DNA methyltransferases and histone-modifying enzymes work in concert with chromatin-remodeling complexes and RNA-guided mechanisms to establish a specific chromatin structure that defines the transcriptional state of rRNA genes. These studies exemplify the mutual dependence and complex crosstalk among different epigenetic players in the alteration of the chromatin structure during the process of gene activation or silencing
    Type of Publication: Journal article published
    PubMed ID: 17613545
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  • 3
    Keywords: RECEPTOR ; Germany ; IN-VIVO ; KINASE ; MODEL ; MODELS ; TYROSINE KINASE ; GENE ; GENE-EXPRESSION ; MICE ; PATIENT ; DOMAIN ; CONTRAST ; BIOLOGY ; MOLECULAR-BIOLOGY ; MATURATION ; STIMULATION ; MOUSE ; MUTANT ; NO ; resistance ; MUTATION ; genetics ; REGION ; REGIONS ; MUTATIONS ; MUSCLE ; PHENOTYPE ; SKELETAL-MUSCLE ; MOUSE MODEL ; REVEALS ; heredity ; ARCHITECTURE ; molecular biology ; molecular ; ADULT ; RE ; PATTERN ; WEIGHT ; DEFECTS ; MUTANTS ; GENOTYPE ; NERVE ; ENGLAND ; NOV ; ACETYLCHOLINE-RECEPTORS ; CONTRACTION ; DOK7 ; INNERVATION ; KINASE DOMAIN ; KINASE MUSK ; SYNAPSE FORMATION
    Abstract: In the muscle-specific tyrosine kinase receptor gene MUSK, a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome (CMS). We generated one mouse line carrying the homozygous missense mutation V789M in musk (musk(V789M/V789M) mice) and a second hemizygous line, resembling the patient genotype, with the V789M mutation on one allele and an allele lacking the kinase domain (musk(V789M/-) mice). We report here that musk(V789M/V789M) mice present no obvious abnormal phenotype regarding weight, muscle function and viability. In contrast, adult musk(V789M/-) mice suffer from severe muscle weakness, exhibit shrinkage of pelvic and scapular regions and hunchback. Musk(V789M/-) diaphragm develops less force upon direct or nerve-induced stimulation. A profound tetanic fade is observed following nerve-evoked muscle contraction, and fatigue resistance is severely impaired upon a train of tetanic nerve stimulations. Electrophysiological measurements indicate that fatigable muscle weakness is due to impaired neurotransmission as observed in a patient suffering from a CMS. The diaphragm of adult musk(V789M/-) mice exhibits pronounced changes in endplate architecture, distribution and innervation pattern. Thus, the missense mutation V789M in MuSK acts as a hypomorphic mutation and leads to insufficiency in MuSK function in musk(V789M/-) mutants. These mutant mice represent valuable models for elucidating the roles of MuSK for synapse formation, maturation and maintenance as well as for studying the pathophysiology of a CMS due to MuSK mutations
    Type of Publication: Journal article published
    PubMed ID: 18718936
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; human ; SYSTEM ; SITE ; GENE ; GENES ; HYBRIDIZATION ; SAMPLE ; PATIENT ; COMPLEX ; BINDING ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; DISORDER ; polymorphism ; VARIANTS ; TARGET ; IN-SITU ; ASSAY ; MUTATION ; genetics ; etiology ; REGION ; REGIONS ; REPLICATION ; HEALTHY ; LUCIFERASE ; heredity ; ANTAGONIST ; MANAGEMENT ; molecular biology ; molecular ; DISORDERS ; VARIANT ; NEURONS ; analysis ; EPITHELIUM ; pooled analysis ; HTR3A ; ENGLAND ; MUTATION ANALYSIS ; DYSFUNCTION ; UNTRANSLATED REGION ; POOLED-ANALYSIS ; UK ; 5-HT3 ; ABDOMINAL-PAIN ; ALOSETRON
    Abstract: Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3'-UTR variant c.*76G 〉 A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G 〉 A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G 〉 A affected binding of miR-510 to the HTR3E 3'-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT-PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D
    Type of Publication: Journal article published
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  • 5
    Keywords: CANCER ; EXPRESSION ; COMBINATION ; DISEASE ; RISK ; GENE ; GENE-EXPRESSION ; IMPACT ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; polymorphism ; single nucleotide polymorphism ; VARIANTS ; gene expression ; NUMBER ; MUTATION ; genetics ; SNP ; colorectal cancer ; COLORECTAL-CANCER ; REGION ; MUTATIONS ; INDIVIDUALS ; SERIES ; HEALTHY ; heredity ; molecular biology ; molecular ; RE ; VARIANT ; INCREASE ; METAANALYSIS ; ALLELES ; LOCUS ; single-nucleotide polymorphism ; ENGLAND ; 8Q24 ; INCREASES ; GENOME-WIDE ASSOCIATION ; association study ; SCAN ; GENOME-WIDE
    Abstract: The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (ORper allele = 1.19; 95% CI: 1.15-1.23; P-trend = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression
    Type of Publication: Journal article published
    PubMed ID: 18753146
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  • 6
    Keywords: CANCER ; MODEL ; COMMON ; RISK ; GENE ; GENES ; BIOLOGY ; ASSOCIATION ; SUSCEPTIBILITY ; VARIANTS ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; ovarian cancer ; OVARIAN-CANCER ; genetics ; SNP ; cancer risk ; REPLICATION ; case-control studies ; molecular biology ; case-control study ; REGRESSION ; VARIANT ; SNPs ; GENOTYPE ; CANCER-RISK ; LOCI ; GENOME-WIDE ASSOCIATION ; genetic association ; Genetic ; Genome-wide association studies ; INVASIVE OVARIAN
    Abstract: Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case-control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially, three SNPs (rs2107425 in MRPL23, rs7313833 in PTHLH, rs3803662 in TNRC9) were weakly associated with ovarian cancer risk and one SNP (rs4954956 in NXPH2) was associated with serous ovarian cancer in non-Hispanic white subjects (P-trend 〈 0.1). These four SNPs were then genotyped in an additional 4060 cases and 6308 controls from eight independent studies. Only rs4954956 was significantly associated with ovarian cancer risk both in the replication study and in combined analyses. This association was stronger for the serous histological subtype [per minor allele odds ratio (OR) 1.07 95% CI 1.01-1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07-1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast cancer susceptibility variants we tested was associated with ovarian cancer risk. Further work will be needed to identify the causal variant associated with rs4954956 or elucidate its function
    Type of Publication: Journal article published
    PubMed ID: 19304784
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  • 7
    Abstract: Mutations in three different genes of phosphorylase kinase (Phk) subunits, PHKA2, PHKB and PHKG2, can give rise to glycogen storage disease of the liver. The autosomal-recessive, liver-specific variant of Phk deficiency is caused by mutations in the gene encoding the testis/liver isoform of the catalytic gamma subunit, PHKG2. To facilitate mutation detection and to improve our understanding of the molecular evolution of Phk subunit isoforms, we have determined the structure of the human PHKG2 gene. The gene extends over 9.5 kilonucleotides and is divided into 10 exons; positions of introns are highly conserved between PHKG2 and the gene of the muscle isoform of the gamma subunit, PHKG1. The beginning of intron 2 harbors a highly informative GGT/GT microsatellite repeat, the first polymorphic marker in the PHKG2 gene at human chromosome 16p11.2-p12.1. Employing the gene sequence, we have identified homozygous translation-terminating mutations, 277delC and Arg44ter, in the two published cases of liver Phk deficiency who developed cirrhosis in childhood. As liver Phk deficiency is generally a benign condition and progression to cirrhosis is very rare, this finding suggests that PHKG2 mutations are associated with an increased cirrhosis risk.
    Type of Publication: Journal article published
    PubMed ID: 9384616
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  • 8
    Abstract: Glycogen storage disease due to phosphorylase kinase deficiency occurs in several variants that differ in mode of inheritance and tissue-specificity. This heterogeneity is suspected to be largely due to mutations affecting different subunits and isoforms of phosphorylase kinase. The gene of the ubiquitously expressed beta subunit, PHKB, was a candidate for involvement in autosomally transmitted phosphorylase kinase deficiency of liver and muscle. To identify such mutations, the complete PHKB coding sequence was amplified by RT-PCR of RNA isolated from blood samples of patients and analyzed by direct sequencing of PCR products. The characterization of mutations was complemented by PCR of genomic DNA. In one female and four male patients, we identified five independent nonsense mutations (Y418ter; R428ter; Y974H+E975ter; Q656ter in two cases), one single-base insertion in codon N421, one splice-site mutation affecting exon 31, and a large deletion involving the loss of exon 8. Although these severe translation-disrupting mutations occur in constitutively expressed sequences of the only known beta subunit gene of phosphorylase kinase, PHKB, they are associated with a surprisingly mild clinical phenotype, affecting virtually only the liver, and relatively high residual enzyme activity of approximately 10%.
    Type of Publication: Journal article published
    PubMed ID: 9215682
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  • 9
    Abstract: In five cases of X-linked liver glycogenosis subtype 2 (XLG2), we have identified mutations in the gene encoding the liver isoform of the phosphorylase kinase alpha subunit (PHKA2). XLG2 is a rare variant of X-linked phosphorylase kinase (Phk) deficiency of the liver. Whereas in the more common form of X-linked hepatic Phk deficiency, XLG1, the enzyme's activity is decreased both in liver and in blood cells, Phk activity in XLG2 is low in liver but normal or even enhanced in blood cells. Although missense, nonsense and splicesite mutations in the PHKA2 gene were recently identified in several cases of XLG1, no mutations have yet been described for XLG2 and a molecular explanation for the peculiar biochemical phenotype of XLG2 has been lacking. All mutations found in the present study result in non-conservative amino acid replacements of residues that are absolutely conserved between the alpha L, alpha M and beta subunits of Phk [H132P, H132Y, R186H (twice) and D299G]. Strikingly, in two pairs of cases the mutations affect the same codon. These results demonstrate that: (i) XLG2 is caused by mutations in PHKA2 and is therefore allelic with XLG1; and (ii) XLG2 mutations appear to cluster in limited sequence regions or even individual codons.
    Type of Publication: Journal article published
    PubMed ID: 8733134
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  • 10
    Keywords: POPULATION ; ASSOCIATION ; SCHIZOPHRENIA ; PERVASIVE DEVELOPMENTAL DISORDERS ; INDIVIDUALS ; SPECTRUM DISORDERS ; Copy number variation ; GENETIC ARCHITECTURE ; NEUROPSYCHIATRIC CONDITIONS ; PTEN MUTATIONS
    Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P 〈 5 x 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P 〈 5 x 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C
    Type of Publication: Journal article published
    PubMed ID: 20663923
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