Biomedical subjects

Bernhard H F Weber

Publications and source records attributed to Bernhard H F Weber.

At least 19 recordsLinked to original sources

PubMed2007

Case-control genetic association study of fibulin-6 (FBLN6 or HMCN1) variants in age-related macular degeneration (AMD).

This article reports a well-powered age-related macular degeneration (AMD) case-control association study in the HMCN1 gene, showing that common variants do not account for a substantial proportion of AMD cases. Thus, the consistent linkage peak observed by several genome-wide linkage scans within the 1q32 region is unlikely to be attributed to polymorphisms at the HMCN1 locus. In addition, the analysis provides comprehensive data suggesting that low-frequency variants encoding possible functional amino acid polymorphisms in the HMCN1 gene may not contribute substantially to disease, although HMCN1 mutations may still confer disease susceptibility in a small subset of patients. Interestingly, the HMCN1 p.Gln5346Arg mutation, which is thought to be a causal mutation in a large AMD pedigree segregating the disease as a single-gene trait, appears to occur in our control cohort as a low-frequency polymorphism with an allele frequency of approximately 0.0026.

Age Factors↗

PubMed2006

Insertion and topology of normal and mutant bestrophin-1 in the endoplasmic reticulum membrane.

The vitelliform macular dystrophy type 2 (VMD2) gene mutated in Best macular dystrophy encodes a 585-amino acid putative transmembrane protein termed bestrophin-1. The vast majority of known disease-associated alterations are of the missense type, which cluster near predicted transmembrane domains (TMDs). To investigate bestrophin-1 membrane topology and to assess consequences of point mutations on membrane integration, we have analyzed the insertion of putative TMDs into the endoplasmic reticulum (ER) membrane. Out of six potential TMDs, our data suggest a topological model of bestrophin-1 with four transmembrane-spanning segments and one large cytoplasmatic loop between putative TMD2 and TMD5. Consequently, a relatively hydrophobic segment containing putative TMD3 (aa 130-149) and TMD4 (aa 179-201) is located within the cytoplasm. Furthermore, we show that three out of 18 disease-associated alterations investigated (I73N, Y85H, F281del) reveal measurable effects on membrane insertion suggesting that defective membrane integration of bestrophin-1 may represent a potential disease mechanism for a small subset of Best macular dystrophy-related mutations.

Animals↗

PubMed2006

Assessment of the contribution of CFH and chromosome 10q26 AMD susceptibility loci in a Russian population isolate.

BACKGROUND/AIMS: A strong association has been confirmed between age-related macular degeneration (AMD) and variants at two independent loci including Tyr402His in the complement factor H (CFH) on 1q32 and Ser69Ala at LOC387715, a hypothetical gene on chromosome 10q26. The contribution of both loci to AMD was investigated in an isolated north-west Russian population. METHODS: Together with a PLEKHA1 variant at 10q26, the CFH Tyr402His and LOC387715 Ser69Ala polymorphisms were genotyped in 155 patients with AMD and 151 age-matched controls. chi(2) and Mantel-Haenszel (M-H) score tests were used to test for association. Sex-adjusted ORs were calculated. RESULTS: The frequency of the Tyr402His C allele was significantly higher in patients with AMD compared with controls (p(M-H)=0.0035). The increased risk observed in patients homozygous for the C allele (OR(HOM)=2.71, 95% CI 1.25 to 5.90) in this indigenous Russian population was considerably lower than that observed in previous western Caucasian populations. A significant increase in the frequency of the LOC387715 variant was observed in patients with late-stage AMD compared with controls (p(M-H)=0.007), with a homozygous OR of 3.47 (95% CI 1.01 to 11.9), although this association was not seen with early-stage AMD. CONCLUSION: The CFH gene contributes to AMD in this Russian population, although the risk conferred is considerably lower in this population than that found in other Western populations. A contribution of LOC387715 to disease in this population is also likely to be of weak effect.

Aged↗

PubMed2006

The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer.

Overexpression of cAMP-dependent protein kinase A (PKA) is a hallmark of the great majority of human cancers including breast cancer. A-kinase anchoring proteins (AKAPs) coordinate the specificity of PKA signalling by localizing the kinase to its subcellular sites. We tested the hypothesis whether the functional amino acid exchange Ile646Val, located in the kinase-binding domain of AKAP10, is a low-penetrance familial breast cancer risk factor. Ile646Val alters the binding of AKAP10 to PKA and is associated with morbidity. The analysis of 787 BRCA1/2 mutation-negative familial breast cancer patients and 993 controls revealed an association of the AKAP10 Ile646Val polymorphism with increased familial breast cancer risk [odds ratio (OR)=1.25, 95% confidence interval (CI) 1.03-1.51, P=0.024]. Our previous study has shown that AKAP13 Lys526Gln is associated with familial breast cancer (OR=1.58). Here, we discovered that carriers of both variants, AKAP10 Ile646Val and AKAP13 Lys526Gln, are at a further enhanced breast cancer risk (OR=2.41, 95% CI 1.30-4.46, P=0.005). PKA is a major target of therapeutic anticancer strategies. Phosphorylation of the estrogen receptor (ER) alpha by PKA induces resistance against the anti-estrogen tamoxifen. Our results indicate for the first time the importance of AKAP10 Ile646Val for familial breast cancer susceptibility. Due to the impact of Ile646Val on the subcellular localization of PKA, it will be interesting to investigate whether this polymorphism influences the effectiveness of PKA and tamoxifen based therapeutic anticancer concepts.

A Kinase Anchor Proteins↗

PubMed2006

Genetic analysis of candidate genes modifying the age-at-onset in Huntington's disease.

The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington's disease (HD) and determines 42-73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.

Acyltransferases↗

PubMed2006

Gross rearrangements in BRCA1 but not BRCA2 play a notable role in predisposition to breast and ovarian cancer in high-risk families of German origin.

A total of 226 index cases from high-risk hereditary breast and ovarian cancer families of German origin who had tested negative for small nucleotide alterations in BRCA1 and BRCA2 were analyzed for gross genomic rearrangements at the two gene loci by the multiplex ligation-dependent probe amplification technique. Six large genomic alterations were identified in BRCA1, while no gross rearrangements were found in BRCA2. The six BRCA1 mutations included two novel mutations including a deletion of exon 5, and a deletion comprising exons 5-7, as well as three distinct gross alterations previously reported, including a deletion of exons 1A, 1B, and 2, two duplications of exon 13, and a deletion of exon 17. To understand the mechanisms underlying the genomic rearrangements within the BRCA1 gene and to provide a simple PCR-based assay for further diagnostic applications, we have defined the molecular breakpoints of the deletion/insertion mutations. In all cases, our data point to a mechanism by which illegitimate crossing over between stretches of direct repeat sequences as small as 9 base pairs (bp) and up to 188 bp may have occurred. Overall, we provide evidence that gross rearrangements within the BRCA1 gene locus may be as frequent as 3% in primarily mutation-negative tested high-risk familial breast and ovarian cancer of German ancestry, while large alterations involving the BRCA2 locus do not appear to play a significant role in disease etiology. These findings have important implications for genetic counseling and testing of high-risk breast and ovarian cancer families.

Adult↗

PubMed2006

Associations of genetic variants in the estrogen receptor coactivators PPARGC1A, PPARGC1B and EP300 with familial breast cancer.

The mitogen effect of the ovarian steroid estrogen is a strong risk factor for breast cancer development. This effect is mainly mediated by the estrogen receptor alpha, a hormone inducible transcription factor, which activates gene expression through recruiting multiple coactivators, such as PPARGC1A, PPARGC1B and EP300. We tested the hypothesis that non-conservative, putative functional amino acid exchanges in PPARGC1A, PPARGC1B and EP300 act as low-penetrance familial breast cancer risk factors. The analysis of 816 BRCA1/2 mutation-negative familial breast cancer patients and 1012 controls revealed an association of the PPARGC1A Thr612Met polymorphism with familial breast cancer (OR = 1.35, 95% CI 1.00-1.81, P = 0.049), high-risk familial breast cancer (OR = 1.51, 95% CI 1.08-2.12, P = 0.017) and bilateral familial breast cancer (OR = 2.30, 95% CI 1.24-4.28, P = 0.009). Logistic regression analyses of the PPARGC1B Ala203Pro variant showed an increased familial breast cancer risk of heterozygous and homozygous variant allele carriers (OR = 1.48, 95% CI 1.15-1.91, P = 0.002). The genotype-combination analysis of the associated PPARGC1A Thr612Met variant and the associated PPARGC1B Ala203Pro variant suggests an allele dose-dependent breast cancer risk (P(trend) = 0.0004). Our results indicate for the first time the importance of inherited variants in the estrogen receptor coactivator genes PPARGC1A and PPARGC1B for familial breast cancer susceptibility. Owing to their impact on estrogen signaling, these polymorphisms might also influence adjuvant anti-estrogen therapy, using agents such as tamoxifen and raloxifen, and outcome of breast cancer patients.

Breast Neoplasms↗

PubMed2006

Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer.

Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature ageing and cancer predisposition. We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance familial breast cancer risk factors. Moreover, we examined the putative impact of p53 MspI 1798G>A, which is completely linked to p53PIN3, a 16 bp insertion/duplication that has been associated with reduced p53 expression, on familial breast cancer risk. Genotyping analyses, performed on 816 BRCA1/2 mutation-negative German familial breast cancer patients and 1012 German controls, revealed a significant association of the WRN Cys1367Arg polymorphism with familial breast cancer (OR = 1.28, 95% CI 1.06-1.54) and high-risk familial breast cancer (OR = 1.32, 95% CI 1.06-1.65). The analysis of p53 MspI 1798G>A, which is completely linked to p53PIN3, showed a significantly increased familial breast cancer risk for carriers of the 16 bp insertion/duplication, following a recessive mode (OR = 2.15, 95% CI = 1.12-4.11). WRN Cys1367Arg, located in the C-terminus, the binding site of p53, is predicted to be damaging. The joint effect of WRN Cys1367Arg and p53 MspI resulted in an increased breast cancer risk compared to the single polymorphisms (OR = 3.39, 95% CI 1.19-9.71). In conclusion, our study indicates the importance of inherited variants in the WRN and p53 genes for familial breast cancer susceptibility.

Adenosine Triphosphatases↗

PubMed2006

Clinical findings in a multigeneration family with autosomal dominant central areolar choroidal dystrophy associated with an Arg195Leu mutation in the peripherin/RDS gene.

OBJECTIVE: To characterize clinical findings associated with a mutation in codon 195 (Arg195Leu) of the peripherin/RDS gene in a large multigeneration family of European decent. METHODS: Sixteen members from 2 generations underwent ophthalmologic examination, including best-corrected visual acuity, examination of the anterior segments, and inspection of the ocular fundus after pharmacologic mydriasis. All affected family members underwent Farnsworth Panel-D15 color testing. Five selected family members with early stages of the disease underwent multifocal electroretinography. Full-field electroretinography was performed in 2 family members with more advanced fundus changes. Finally, former patients' records and fundus images were analyzed to determine the course of the disease in affected individuals. RESULTS: Nine family members in 2 generations were diagnosed as having autosomal dominant central areolar choroidal dystrophy. The family demonstrated an age-dependent increase of central granular fundus abnormalities with progressive development of geographic atrophy. Interindividual phenotypic variability was apparent and ranged from predominantly drusenlike depositions to single perifoveal pigment clumps. Age of onset of visual disturbances varied between 27 and 48 years. All individuals who manifested signs of disease were found to carry an Arg195Leu mutation in the peripherin/RDS gene. CONCLUSIONS: Age of onset, progression of the disease, and characteristic fundus abnormalities share similarities to previous reports on families with central areolar choroidal dystrophy associated with peripherin/RDS gene mutations in codons 172, 142, and 195, respectively. However, striking variability in individual phenotypic findings and age of onset in our family suggests that additional factors that modify the defined peripherin/RDS gene mutation Arg195Leu likely influence the severity of the disease. CLINICAL RELEVANCE: Caution should be advised in predicting the clinical course and severity of the disease based solely on a specific mutation in the peripherin/RDS gene.

Adolescent↗

PubMed2006

Late-onset central areolar choroidal dystrophy caused by a heterozygous frame-shift mutation affecting codon 307 of the peripherin/RDS gene.

Mutations in the peripherin/RDS gene have been identified in families with various retinopathies including those affecting primarily the macula and those restricted to the retinal periphery. Here, we describe the clinical findings of two sisters with late-onset central areolar choroidal dystrophy (CACD). The two siblings underwent genetic testing and were found to be carriers of a heterozygous frame-shift mutation 920delT affecting codon 307 of the peripherin/RDS gene and resulting in a truncated, likely functionless, protein with an altered C-terminus (Leu307fsX83). The identical mutation has previously been reported to cause slowly progressive autosomal dominant retinitis pigmentosa. In our two patients, the Leu307fsX83 mutation accounts for an unusually mild form of retinal degeneration.

Aged↗

PubMed2005

The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease.

An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.

Age of Onset↗

PubMed2005

Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk.

Age-related macular degeneration (AMD) is a multifactorial disease and a prevalent cause of visual impairment in developed countries. Risk factors include environmental components and genetic determinants. The complement factor H (CFH) has been the first major susceptibility gene for AMD identified within 1q32. Here, we focused on a second region of interest in 10q26 where a recent meta-analysis revealed strongest evidence for linkage to AMD at a genome-wide significance level. Within an interval of 22 Mb, we have analyzed 93 single nucleotide polymorphisms for allelic association with AMD in two independent case-control cohorts of German origin (AMD(combined) n=1166; controls(combined) n=945). Significant association was found across a 60 kb region of high linkage disequilibrium harboring two genes PLEKHA1 and hypothetical LOC387715. The strongest association (P=10(-34)) centered over a frequent coding polymorphism, Ala69Ser, at LOC387715, strongly implicating this gene in the pathogenesis of AMD. Besides abundant expression in placenta, we demonstrate weak expression of LOC387715 in the human retina. At present, however, there is no functional information on this gene, which appears to have evolved recently within the primate lineage. The joint contribution of the common risk allele at LOC387715, Ala69Ser, and at CFH, Tyr402His, was assessed in our case-control population, which suggests an additive model indicating an independent contribution of the two gene loci to disease risk. Our data show a disease odds ratio of 57.6 (95% CI: 37.2, 89.0) conferred by homozygosity for risk alleles at both CFH and LOC387715 when compared with the baseline non-risk genotype.

Base Sequence↗

PubMed2005

Meta-analysis of genome scans of age-related macular degeneration.

A genetic contribution to the development of age-related macular degeneration (AMD) is well established. Several genome-wide linkage studies have identified a number of putative susceptibility loci for AMD but only a few of these regions have been replicated in independent studies. Here, we perform a meta-analysis of six AMD genome screens using the genome-scan meta-analysis method, which allows linkage results from several studies to be combined, providing greater power to identify regions that show only weak evidence for linkage in individual studies. Results from non-parametric analysis for a broad AMD clinical phenotype (including two studies with quantitative traits) were extracted. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to maximum evidence for linkage within each bin. Bin ranks were weighted according to study size and summed across all studies; the summed rank (SR) for each bin was assessed empirically for significance using permutation methods. A high SR indicates a region with consistent evidence for linkage across studies. The strongest evidence for an AMD susceptibility locus was found on chromosome 10q26 where genome-wide significant linkage was observed (P=0.00025). Several other regions met the empirical significance criteria for bins likely to contain linked loci including adjacent pairs of bins on chromosomes 1q, 2p, 3p and 16. Several of the regions identified here showed only weak evidence for linkage in the individual studies. These results will help prioritize regions for future positional and functional candidate gene studies in AMD.

Aging↗

PubMed2005

Membrane-associated guanylate kinase proteins MPP4 and MPP5 associate with Veli3 at distinct intercellular junctions of the neurosensory retina.

MPP4 and MPP5 are closely related members of the p55-subfamily of membrane-associated guanylate kinases (MAGUKs) known to mediate the assembly of protein complexes at the plasma membrane of cell-cell junctions. Both MPP4 and MPP5 have been implicated in retinal function; however, their specific roles in the cellular mechanisms underlying vision are largely unknown. Here, we generated specific poly- and monoclonal antibodies against the two proteins and show that MPP4 and MPP5 are localized at distinct sites of cell-cell contact in the mouse retina. While MPP4 is a component of the synaptic terminals of photoreceptors, MPP5 exclusively localizes to apical membrane domains of the outer limiting membrane (OLM) junctions. The vertebrate homologs of Caenorhabditis elegans lin-7, Veli1, -2, and -3, have previously been identified as putative binding partners of MPP5. In this study, we show that MPP4 directly interacts with the Veli proteins via L27 heterodimerization in vitro. In addition, two of the three Veli isoforms, Veli1 and -3, are demonstrated to be expressed in the mouse retina. Immunofluorescence microscopy reveals extensive colocalization of Veli3 with both MPP4 and MPP5. This association of Veli3 with either MPP4 or MPP5 suggests that the MAGUKs recruit Veli3 and its binding partners to different cellular regions of the retina where they may participate in the organization of specialized intercellular junctions.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Late onset is common in best macular dystrophy associated with VMD2 gene mutations.

PURPOSE: To perform a detailed morphologic and functional evaluation of Best macular dystrophy (BMD) associated with mutations in the VMD2 gene. DESIGN: Retrospective study. PARTICIPANTS: The records of 16 patients with BMD and heterozygous VMD2 mutations (group 1) and 5 patients with Best-like lesions with no detectable disease-associated alterations in the VMD2 gene (group 2) were evaluated retrospectively. METHODS: The data were reviewed regarding visual acuity (VA), color vision, perimetry, autofluorescence of the retinal pigment epithelium (RPE), fluorescein angiography, electro-oculography (EOG), and full-field electroretinography (ERG) and multifocal ERG (mfERG). MAIN OUTCOME MEASURES: VMD2 mutations, age at onset of BMD, RPE autofluorescence, EOG, ERG, and mfERG. RESULTS: The mean age of the patients in group 1 was 47.1 years (range, 16.7-86.5), and age at onset varied between 5 and 58 years (median, 42.0). Visual acuity ranged between 20/16 and 20/400 (median, 20/40). No association existed between the specific nature of the VMD2 mutation and disease onset or expressivity. Retinal pigment epithelium autofluorescence was increased corresponding to ophthalmoscopically visible yellow material, whereas it was decreased in the atrophic stage of BMD. Electro-oculography light rise was reduced in 18 of 19 eyes. Electroretinography amplitudes were normal in 3 patients and reduced in 6 patients. Multifocal ERG revealed in 10 of 20 eyes a central amplitude reduction and in 7 eyes a generalized one. There were no marked differences in clinical and functional findings between the patients in groups 1 and 2, except that the mean age of the patients in group 2 was higher (64.0 years [range, 45.7-80.6]) and the median VA lower (20/50 [range, 20/32-20/320]). CONCLUSIONS: The onset of BMD is highly variable and occurred in the majority of patients after the second decade of life. Best-like lesions may develop in older patients without associated VMD2 mutations. Those manifestations may be related to a specific form of age-related macular degeneration. This article contains additional online-only material available at .

Adolescent↗

PubMed2005

Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis.

X-linked juvenile retinoschisis (RS) is a common cause of juvenile macular degeneration in males. RS is characterized by cystic spoke-wheel-like maculopathy, peripheral schisis, and a negative (b-wave more reduced than a-wave) electroretinogram (ERG). These symptoms are due to mutations in the RS1 gene in Xp22.2 leading to loss of functional protein. No medical treatment is currently available. We show here that in an Rs1h-deficient mouse model of human RS, delivery of the human RS1 cDNA with an AAV vector restored expression of retinoschisin to both photoreceptors and the inner retina essentially identical to that seen in wild-type mice. More importantly, unlike an earlier study with a different AAV vector and promoter, this work shows for the first time that therapeutic gene delivery using a highly specific AAV5-opsin promoter vector leads to progressive and significant improvement in both retinal function (ERG) and morphology, with preservation of photoreceptor cells that, without treatment, progressively degenerate.

Animals↗

PubMed2004

Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin.

Li-Fraumeni Syndrome (LFS) is a rare cancer syndrome caused by mutations in the TP53 gene. A number of tumor-associated germline mutations have been described in individuals from various ethnic origins although, thus far, none in affected individuals of German descent. Our work aimed to detect germline mutations in the TP53 gene in five index cases of German and Swiss origin with cancers typical of Li-Fraumeni syndrome. We analyzed all ten coding exons of the TP53 gene by direct sequencing of PCR products. We identified five mutations of which three were found in families with a strong history of LFS in several generations while two likely came about de novo. The five mutations include two missense mutations in exon 4 (Gly105Cys) and exon 7 (Arg248Gln), one deletion of 11 base pairs encompassing the splice acceptor sequence of exon 6 (IVS5-11_-1 del), one nonsense mutation in exon 6 (Arg196Stop), and one duplication of 4 base pairs in exon 8 (1020_1023dupCTGC). The functional consequence of the IVS5-11_-1del mutation on splicing of pre-mRNA was investigated by an in vitro assay. Our study reports the first germline mutations in patients of German and Swiss origin with LFS-related tumors. The frequent identification of de novo germline mutations emphasizes the importance of mutational analyses of the TP53 gene particularly in young patients with malignancies typical for LFS, but without a positive family history of this tumor syndrome.

Adolescent↗

PubMed2004

The Retinome - defining a reference transcriptome of the adult mammalian retina/retinal pigment epithelium.

BACKGROUND: The mammalian retina is a valuable model system to study neuronal biology in health and disease. To obtain insight into intrinsic processes of the retina, great efforts are directed towards the identification and characterization of transcripts with functional relevance to this tissue. RESULTS: With the goal to assemble a first genome-wide reference transcriptome of the adult mammalian retina, referred to as the retinome, we have extracted 13,037 non-redundant annotated genes from nearly 500,000 published datasets on redundant retina/retinal pigment epithelium (RPE) transcripts. The data were generated from 27 independent studies employing a wide range of molecular and biocomputational approaches. Comparison to known retina-/RPE-specific pathways and established retinal gene networks suggest that the reference retinome may represent up to 90% of the retinal transcripts. We show that the distribution of retinal genes along the chromosomes is not random but exhibits a higher order organization closely following the previously observed clustering of genes with increased expression. CONCLUSION: The genome wide retinome map offers a rational basis for selecting suggestive candidate genes for hereditary as well as complex retinal diseases facilitating elaborate studies into normal and pathological pathways. To make this unique resource freely available we have built a database providing a query interface to the reference retinome 1.

Adult↗