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ABSTRACT: We describe a female patient with mild lissencephaly (pachygyria), severe intellectual disability, and facial dysmorphisms with an inverted 1.4 Mb microduplication of chromosome 17p13.3. The 17p13.3 microduplication syndrome is associated with mild intellectual disabiltiy and contains, among others, the PAFAH1B1 (LIS1) gene, whereas microdeletions of the same segment cause Miller-Dieker syndrome (MDS) with severe to profound retardation. The duplication identified in our patient encompasses 29 genes, including CRK and YWHAE. The proximal breakpoint of the duplication is located in the first intron of the PAFAH1B1 gene. Analysis of total RNA showed that only one PAFAH1B1 allele is expressed. Therefore, this patient has a unique alteration: a duplication including YWHAE and CRK and haploinsufficiency of PAFAH1B1. Overexpression of YWHAE is associated with macrosomia, mild developmental delay, autism and facial dysmorphisms, and deletion of PAFAH1B1 alone leads to isolated lissencephaly (ILS). The patient described here shares features with MDS, but she is affected to a lesser degree. Her facial features are similar to MDS, and she has manifestations seen in other cases with YWHAE duplication. © 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A 04/2013; · 2.39 Impact Factor
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Karin Hardt,
Sven Boris Heick,
Beate Betz, Timm Goecke,
Haniyeh Yazdanparast,
Robin Küppers,
Kati Servan,
Verena Steinke,
Nils Rahner,
Monika Morak,
Elke Holinski-Feder,
Christoph Engel,
Gabriela Möslein,
Hans-Konrad Schackert,
Magnus von Knebel Doeberitz,
Christian Pox,
Johannes H Hegemann,
Brigitte Royer-Pokora
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ABSTRACT: Missense mutations of the DNA mismatch repair gene MLH1 are found in a significant fraction of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) and their pathogenicity often remains unclear. We report here all 88 MLH1 missense variants identified in families from the German HNPCC consortium with clinical details of these patients/families. We investigated 23 MLH1 missense variants by two functional in vivo assays in yeast; seven map to the ATPase and 16 to the protein interaction domain. In the yeast-2-hybrid (Y2H) assay three variants in the ATPase and twelve variants in the interaction domain showed no or a reduced interaction with PMS2; seven showed a normal and one a significantly higher interaction. Using the Lys2A (14) reporter system to study the dominant negative mutator effect (DNE), 16 variants showed no or a low mutator effect, suggesting that these are nonfunctional, three were intermediate and four wild type in this assay. The DNE and Y2H results were concordant for all variants in the interaction domain, whereas slightly divergent results were obtained for variants in the ATPase domain. Analysis of the stability of the missense proteins in yeast and human embryonic kidney cells (293T) revealed a very low expression for seven of the variants in yeast and for nine in human cells. In total 15 variants were classified as deleterious, five were classified as variants of unclassified significance (VUS) and three were basically normal in the functional assays, P603R, K618R, Q689R, suggesting that these are neutral.
Familial Cancer 03/2011; 10(2):273-84. · 1.30 Impact Factor
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Stefanie Huhn,
Dierk Ingelfinger,
Justo Lorenzo Bermejo,
Melanie Bevier,
Barbara Pardini,
Alessio Naccarati,
Verena Steinke,
Nils Rahner,
Elke Holinski-Feder,
Monika Morak, [......],
Kubilay Demir,
Cristina-Maria Cruciat,
Rebecca Renneberg,
Wolfgang Huber,
Christof Niehrs,
Michael Boutros,
Peter Propping,
Pavel Vodièka,
Kari Hemminki,
Asta Försti
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ABSTRACT: Colorectal cancer (CRC) is a complex disease related to environmental and genetic risk factors. Several studies have shown that susceptibility to complex diseases can be mediated by ancestral alleles. Using RNAi screening, CTNNBL1 was identified as a putative regulator of the Wnt signaling pathway, which plays a key role in colorectal carcinogenesis. Recently, single nucleotide polymorphisms (SNPs) in CTNNBL1 have been associated with obesity, a known risk factor for CRC. We investigated whether genetic variation in CTNNBL1 affects susceptibility to CRC and tested for signals of recent selection. We applied a tagging SNP approach that cover all known common variation in CTNNBL1 (allele frequency >5%; r(2)>0.8). A case-control study was carried out using two well-characterized study populations: a hospital-based Czech population composed of 751 sporadic cases and 755 controls and a family/early onset-based German population (697 cases and 644 controls). Genotyping was performed using allele specific PCR based TaqMan® assays (Applied Biosystems, Weiterstadt, Germany). In the Czech cohort, containing sporadic cases, the ancestral alleles of three SNPs showed evidence of association with CRC: rs2344481 (OR 1.44, 95%CI 1.06-1.95, dominant model), rs2281148 (OR 0.59, 95%CI 0.36-0.96, dominant model) and rs2235460 (OR 1.38, 95%CI 1.01-1.89, AA vs. GG). The associations were less prominent in the family/early onset-based German cohort. Data derived from several databases and statistical tests consistently pointed to a likely shaping of CTNNBL1 by positive selection. Further studies are needed to identify the actual function of CTNNBL1 and to validate the association results in other populations.
International Journal of Molecular Epidemiology and Genetics 01/2011; 2(1):36-50.
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Jesús Lascorz,
Asta Försti,
Bowang Chen,
Stephan Buch,
Verena Steinke,
Nils Rahner,
Elke Holinski-Feder,
Monika Morak,
Hans K Schackert,
Heike Görgens, [......],
Clemens D Bröring,
Henry Völzke,
Clemens Schafmayer,
Pavel Vodicka,
Jenny Chang-Claude,
Hermann Brenner,
Barbara Burwinkel,
Peter Propping,
Jochen Hampe,
Kari Hemminki
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ABSTRACT: Genetic susceptibility accounts for approximately 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value < 10(-3)). The risk of CRC increased significantly with an increasing number of risk alleles in seven genes involved in MAPK signalling events (P(trend) = 2.2 x 10(-16), OR(per allele) = 1.34, 95% CI 1.11-1.61).
Carcinogenesis 09/2010; 31(9):1612-9. · 5.70 Impact Factor
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Sibylle Eigelshoven,
Gitta Kameda,
Anne-Katrin Kortüm,
Simone Hübsch,
Wolfgang Angerstein,
Preeti Singh,
Renate Vöhringer, Timm Goecke,
Ertan Mayatepek,
Thomas Ruzicka,
Gabriele Wildhardt,
Thomas Meissner,
Roland Kruse
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ABSTRACT: We report a 3-year-old girl with autosomal dominant inherited Waardenburg syndrome type I showing circumscribed hypopigmentation of the skin, heterochromia iridis, sensorineural deafness, and dental aberrations. Clinical diagnosis was confirmed by the identification of an underlying missense mutation (C811T) in the PAX3 gene. Early diagnosis of Waardenburg syndrome among children with pigment anomalies enables a successful interdisciplinary medical care.
Pediatric Dermatology 11/2009; 26(6):759-61. · 1.07 Impact Factor
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Heidi Salloch,
Anke Reinacher-Schick,
Karsten Schulmann,
Christian Pox,
Jörg Willert,
Andrea Tannapfel,
Stefan Heringlake, Timm O Goecke,
Stefan Aretz,
Susanne Stemmler,
Wolff Schmiegel
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ABSTRACT: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant polyposis syndrome caused by STK11 germline mutations. PJS is associated with an increased risk of cancer. In our cohort, clinical and phenotypic parameters were correlated with genotypic findings and patients were prospectively followed by surveillance.
Thirty-one patients treated between 2000 and 2006, were evaluated. STK11 genotyping was performed and phenotypes of patients with truncating (TM) and nontruncating mutations (NTM) were compared.
Median age at first symptoms was 11 years and complications occurred before the age of ten in 42% of patients. STK11 mutations were detected in 16 of 22 families (12 TM; four NTM). Patients with TM had more surgical gastrointestinal (GI) interventions (p = 0.021), and female patients in the TM group had an increased risk of undergoing gynecological surgery (p = 0.016). Also, there was a trend towards a higher polyp count (p = 0.11) and earlier age at first polypectomy (p = 0.13) in the TM group. Ten carcinomas were detected in six patients resulting in a cancer risk of 65% up to the age of 65 years. Patients with TM tended to develop more cancers (p = 0.10). Importantly, our surveillance strategy used detected 50% of cancers (n = 5) at an early potentially curable stage.
Our study shows that almost half of PJ patients have complications early in life independent of mutational status. Patients with TM require more surgical GI interventions and tend to develop more polyps and cancers. Furthermore, close surveillance detects early stage cancers in patients. We propose that surveillance should be started as early as 8 years in all patients to avoid complications. Moreover, patients with TM may benefit from surveillance at shorter intervals.
International Journal of Colorectal Disease 10/2009; 25(1):97-107. · 2.38 Impact Factor
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ABSTRACT: Hereditary non-polyposis colorectal cancer, an autosomal dominant predisposition to colorectal cancer and other malignancies, is caused by inactivating mutations of DNA mismatch repair genes, mainly MLH1 and MSH2. Missense mutations affect protein structure or function, but may also cause aberrant splicing, if located within splice sites (ss) or cis-acting sequences of splicing regulatory proteins, i.e., exonic splicing enhancers or exonic splicing silencers. Despite significant progress of ss scoring algorithms, the prediction for the impact of mutations on splicing is still unsatisfactory. For this study, we assessed ten ss and nine missense mutations outside ss in MLH1 and MSH2, including eleven newly identified mutations, and experimentally analyzed their effect at the RNA level. We additionally tested and compared the reliability of several web-based programs for the prediction of splicing outcome for these mutations.
Journal of Cancer Research and Clinical Oncology 09/2009; 136(1):123-34. · 2.56 Impact Factor
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Bernd Frank,
Barbara Burwinkel,
Justo Lorenzo Bermejo,
Asta Försti,
Kari Hemminki,
Richard Houlston,
Elisabeth Mangold,
Nils Rahner,
Waltraut Friedl,
Nicolaus Friedrichs, [......],
Hans K Schackert,
Stefan Krüger, Timm Goecke,
Gabriela Moeslein,
Matthias Kloor,
Johannes Gebert,
Erdmute Kunstmann,
Karsten Schulmann,
Josef Rüschoff,
Peter Propping
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ABSTRACT: Ten non-synonymous single nucleotide polymorphisms (nsSNPs), which were recently associated with colorectal cancer risk in a comprehensive, array based study (AKAP9 M463I, DKK3 G335R, AMPD1 Q12X, LIPC L356F, PSMB9 V32I, THBS1 N700S, CA6 S90G, ASCC3 C1995S, DHX36 S416C and CPA4 G303C) were re-evaluated in the present study based on 626 German familial non-HNPCC colorectal cancer patients and 736 healthy controls. No associations of any of the 10 nsSNPs with colorectal cancer could be replicated. The combined analyses indicated that further research based on additional independent samples is required.
Cancer letters 08/2008; 271(1):153-7. · 4.86 Impact Factor
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ABSTRACT: Congenital central hypoventilation syndrome (CCHS), a rare disorder typically presenting in the newborn period, results in over 90% of cases from PHOX2B polyalanine repeat mutations. It is characterized by alveolar hypoventilation, symptoms of autonomic nervous system dysregulation, and in a subset of cases Hirschsprung's disease and, later, tumors of neural crest origin. We describe a preterm infant with severe phenotype of CCHS and hyperinsulinism. A novel de novo heterozygote missence mutation (Gly68Cys) in the PHOX2B gene could be identified. Based on the observation of three patients presenting with the combination of congenital hyperinsulinism and CCHS, hyperinsulinism might represent an additional clinical feature of CCHS.
Journal of Human Genetics 02/2008; 53(6):573-7. · 2.57 Impact Factor
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Timm Goecke,
Karsten Schulmann,
Christoph Engel,
Elke Holinski-Feder,
Constanze Pagenstecher,
Hans K Schackert,
Matthias Kloor,
Erdmute Kunstmann,
Holger Vogelsang,
Gisela Keller,
Wolfgang Dietmaier,
Elisabeth Mangold,
Nicolaus Friedrichs,
Peter Propping,
Stefan Krüger,
Johannes Gebert,
Wolff Schmiegel,
Josef Rueschoff,
Markus Loeffler,
Gabriela Moeslein
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ABSTRACT: Lynch syndrome is linked to germline mutations in mismatch repair genes. We analyzed the genotype-phenotype correlations in the largest cohort so far reported.
Following standard algorithms, we identified 281 of 574 unrelated families with deleterious germline mutations in MLH1 (n = 124) or MSH2 (n = 157). A total of 988 patients with 1,381 cancers were included in this analysis.
We identified 181 and 259 individuals with proven or obligatory and 254 and 294 with assumed MLH1 and MSH2 mutations, respectively. Age at diagnosis was younger both in regard to first cancer (40 v 43 years; P < .009) and to first colorectal cancer (CRC; 41 v 44 years; P = .004) in MLH1 (n = 435) versus MSH2 (n = 553) mutation carriers. In both groups, rectal cancers were remarkably frequent, and the time span between first and second CRC was smaller if the first primary occurred left sided. Gastric cancer was the third most frequent malignancy occurring without a similarly affected relative in most cases. All prostate cancers occurred in MSH2 mutation carriers.
The proportion of rectal cancers and shorter time span to metachronous cancers indicates the need for a defined treatment strategy for primary rectal cancers in hereditary nonpolyposis colorectal cancer patients. Male MLH1 mutation carriers require earlier colonoscopy beginning at age 20 years. We propose regular gastric surveillance starting at age 35 years, regardless of the familial occurrence of this cancer. The association of prostate cancer with MSH2 mutations should be taken into consideration both for clinical and genetic counseling practice.
Journal of Clinical Oncology 09/2006; 24(26):4285-92. · 18.37 Impact Factor
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Barbara Theresia Weis-Müller,
Olga Modlich,
Irina Drobinskaya,
Derya Unay,
Rita Huber,
Hans Bojar,
Jochen D Schipke,
Peter Feindt,
Emmeran Gams,
Wolfram Müller, Timm Goecke,
Wilhelm Sandmann
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ABSTRACT: We compared gene expression profiles in acutely dissected aorta with those in normal control aorta.
Ascending aorta specimen from patients with an acute Stanford A-dissection were taken during surgery and compared with those from normal ascending aorta from multiorgan donors using the BD Atlas Human1.2 Array I, BD Atlas Human Cardiovascular Array and the Affymetrix HG-U133A GeneChip. For analysis only genes with strong signals of more than 70 percent of the mean signal of all spots on the array were accepted as being expressed. Quantitative real-time polymerase chain reaction (RT-PCR) was used to confirm regulation of expression of a subset of 24 genes known to be involved in aortic structure and function.
According to our definition expression profiling of aorta tissue specimens revealed an expression of 19.1% to 23.5% of the genes listed on the arrays. Of those 15.7% to 28.9% were differently expressed in dissected and control aorta specimens. Several genes that encode for extracellular matrix components such as collagen IV alpha2 and -alpha5, collagen VI alpha3, collagen XIV alpha1, collagen XVIII alpha1 and elastin were down-regulated in aortic dissection, whereas levels of matrix metalloproteinases-11, -14 and -19 were increased. Some genes coding for cell to cell adhesion, cell to matrix signaling (e.g., polycystin1 and -2), cytoskeleton, as well as several myofibrillar genes (e.g., alpha-actinin, tropomyosin, gelsolin) were found to be down-regulated. Not surprisingly, some genes associated with chronic inflammation such as interleukin -2, -6 and -8, were up-regulated in dissection.
Our results demonstrate the complexity of the dissecting process on a molecular level. Genes coding for the integrity and strength of the aortic wall were down-regulated whereas components of inflammatory response were up-regulated. Altered patterns of gene expression indicate a pre-existing structural failure, which is probably a consequence of insufficient remodeling of the aortic wall resulting in further aortic dissection.
Journal of Translational Medicine 02/2006; 4:29. · 3.41 Impact Factor
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Elisabeth Mangold,
Constanze Pagenstecher,
Waltraut Friedl,
Micaela Mathiak,
Reinhard Buettner,
Christoph Engel,
Markus Loeffler,
Elke Holinski-Feder,
Yvonne Müller-Koch,
Gisela Keller, [......],
Stefan Krüger, Timm Goecke,
Gabriela Moeslein,
Matthias Kloor,
Johannes Gebert,
Erdmute Kunstmann,
Karsten Schulmann,
Josef Rüschoff,
Peter Propping,
the German HNPCC Consortium
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ABSTRACT: Mutations in DNA MMR genes, mainly MSH2 and MLH1, account for the majority of HNPCC, an autosomal dominant predisposition to colorectal cancer and other malignancies. The evaluation of many questions regarding HNPCC requires clinically and genetically well-characterized HNPCC patient cohorts of reasonable size. One main focus of this multicenter study is the evaluation of the mutation spectrum and mutation frequencies in a large HNPCC cohort in Germany; 1,721 unrelated patients, mainly of German descent, who met the Bethesda criteria were included in the study. In tumor samples of 1,377 patients, microsatellite analysis was successfully performed and the results were applied to select patients eligible for mutation analysis. In the patients meeting the strict Amsterdam criteria (AC) for HNPCC, 72% of the tumors exhibited high microsatellite instability (MSI-H) while only 37% of the tumors from patients fulfilling the less stringent criteria showed MSI-H; 454 index patients (406 MSI-H and 48 meeting the AC of whom no tumor samples were available) were screened for small mutations. In 134 index patients, a pathogenic MSH2 mutation, and in 118 patients, a pathogenic MLH1 mutation was identified (overall detection rate for pathogenic mutations 56%). One hundred sixty distinct mutations were detected, of which 86 are novel mutations. Noteworthy is that 2 mutations were over-represented in our patient series: MSH2,c.942+3A>T and MLH1,c.1489_1490insC, which account for 11% and 18% of the MSH2 and MLH1 mutations, respectively. A subset of 238 patients was screened for large genomic deletions. In 24 (10%) patients, a deletion was found. In 72 patients, only unspecified variants were found. Our findings demonstrate that preselection by microsatellite analysis substantially raises mutation detection rates in patients not meeting the AC. As a mutation detection strategy for German HNPCC patients, we recommend to start with screening for large genomic deletions and to continue by screening for common mutations in exon 5 of MSH2 and exon 13 of MLH1 before searching for small mutations in the remaining exons. © 2005 Wiley-Liss, Inc.
International Journal of Cancer 09/2005; 116(5):692 - 702. · 5.44 Impact Factor
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Elisabeth Mangold,
Constanze Pagenstecher,
Waltraut Friedl,
Micaela Mathiak,
Reinhard Buettner,
Christoph Engel,
Markus Loeffler,
Elke Holinski-Feder,
Yvonne Müller-Koch,
Gisela Keller,
Hans K Schackert,
Stefan Krüger, Timm Goecke,
Gabriela Moeslein,
Matthias Kloor,
Johannes Gebert,
Erdmute Kunstmann,
Karsten Schulmann,
Josef Rüschoff,
Peter Propping
[show abstract]
[hide abstract]
ABSTRACT: Mutations in DNA MMR genes, mainly MSH2 and MLH1, account for the majority of HNPCC, an autosomal dominant predisposition to colorectal cancer and other malignancies. The evaluation of many questions regarding HNPCC requires clinically and genetically well-characterized HNPCC patient cohorts of reasonable size. One main focus of this multicenter study is the evaluation of the mutation spectrum and mutation frequencies in a large HNPCC cohort in Germany; 1,721 unrelated patients, mainly of German descent, who met the Bethesda criteria were included in the study. In tumor samples of 1,377 patients, microsatellite analysis was successfully performed and the results were applied to select patients eligible for mutation analysis. In the patients meeting the strict Amsterdam criteria (AC) for HNPCC, 72% of the tumors exhibited high microsatellite instability (MSI-H) while only 37% of the tumors from patients fulfilling the less stringent criteria showed MSI-H; 454 index patients (406 MSI-H and 48 meeting the AC of whom no tumor samples were available) were screened for small mutations. In 134 index patients, a pathogenic MSH2 mutation, and in 118 patients, a pathogenic MLH1 mutation was identified (overall detection rate for pathogenic mutations 56%). One hundred sixty distinct mutations were detected, of which 86 are novel mutations. Noteworthy is that 2 mutations were over-represented in our patient series: MSH2,c.942+3A>T and MLH1,c.1489_1490insC, which account for 11% and 18% of the MSH2 and MLH1 mutations, respectively. A subset of 238 patients was screened for large genomic deletions. In 24 (10%) patients, a deletion was found. In 72 patients, only unspecified variants were found. Our findings demonstrate that preselection by microsatellite analysis substantially raises mutation detection rates in patients not meeting the AC. As a mutation detection strategy for German HNPCC patients, we recommend to start with screening for large genomic deletions and to continue by screening for common mutations in exon 5 of MSH2 and exon 13 of MLH1 before searching for small mutations in the remaining exons.
International Journal of Cancer 09/2005; 116(5):692-702. · 5.44 Impact Factor
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Human Genetics 06/2005; 116(6):541. · 5.07 Impact Factor
