Browsing by Subject "PHENOTYPE"

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  • Vakkilainen, Svetlana; Constantini, Alice; Taskinen, Mervi; Wartiovaara-Kautto, Ulla; Mäkitie, Outi (2019)
  • Harris, Elizabeth; Töpf, Ana; Vihola, Anna; Evilä, Anni; Barresi, Rita; Hudson, Judith; Hackman, Peter; Herron, Brian; MacArthur, Daniel; Lochmüller, Hanns; Bushby, Kate; Udd, Bjarne; Straub, Volker (2017)
    Mutations in the gene encoding the giant skeletal muscle protein titin are associated with a variety of muscle disorders, including recessive congenital myopathies cardiomyopathy, limb girdle muscular dystrophy (LGMD) and late onset dominant distal myopathy. Heterozygous truncating mutations have also been linked to dilated cardiomyopathy. The phenotypic spectrum of titinopathies is emerging and expanding, as next generation sequencing techniques make this large gene amenable to sequencing. We undertook whole exome sequencing in four individuals with LGMD. An essential splice site mutation, previously reported in dilated cardiomyopathy, was identified in all families in combination with a second truncating mutation. Affected individuals presented with childhood onset proximal weakness associated with joint contractures and elevated CK. Cardiac dysfunction was present in two individuals. Muscle biopsy showed increased internal nuclei and immunoblotting identified reduction or absence of calpain-3 and demonstrated a marked reduction of C-terminal titin fragments. We confirm the co-occurrence of cardiac and skeletal myopathies associated with recessive truncating titin mutations. Compound heterozygosity of a truncating mutation previously associated with dilated cardiomyopathy and a 'second truncation' in TTN was identified as causative in our skeletal myopathy patients. These findings add to the complexity of interpretation and genetic counselling for titin mutations. (C) 2017 Elsevier B.V. All rights reserved.
  • Vakkilainen, Svetlana; Taskinen, Mervi; Klemetti, Paula; Pukkala, Eero; Mäkitie, Outi (2019)
    Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985-1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%, n = 46) manifested no symptoms of immunodeficiency during follow-up while 19% (n = 15) and 24% (n = 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95% CI = 4.3-11); most commonly from malignancy (n = 7, SMR = 10, 95% CI = 4.1-21) and lung disease (n = 4, SMR = 46, 95% CI = 9.5-130). Mortality associated with birth length below-4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95% CI = 1.5-20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio= 3.9, 95% CI = 1.3-11), Hirschsprung disease (odds ratio (OR) 7.2, 95% CI = 1.04-55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95% CI = 1.3-43/2.6-140) and autoimmunity in adulthood (OR = 39, 95% CI = 3.5-430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.
  • Lahtinen, Alexandra; Puttonen, Sampsa; Vanttola, Päivi; Viitasalo, Katriina; Sulkava, Sonja; Pervjakova, Natalia; Joensuu, Anni; Salo, Perttu; Toivola, Auli; Härmä, Mikko; Milani, Lili; Perola, Markus; Paunio, Tiina (2019)
    Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 +/- 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 +/- 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value <0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.
  • Yasin, Samina; Mustafa, Saima; Ayesha, Arzoo; Latif, Muhammad; Hassan, Mubashir; Faisal, Muhammad; Mäkitie, Outi; Iqbal, Furhan; Naz, Sadaf (2020)
  • Wendt, Frank R.; Novroski, Nicole M. M.; Rahikainen, Anna-Liina; Sajantila, Antti; Budowle, Bruce (2019)
    Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.
  • Vakkilainen, Svetlana; Mäkitie, Riikka; Klemetti, Paula; Valta, Helena; Taskinen, Mervi; Husebye, Eystein Sverre; Mäkitie, Outi (2018)
    Background: Mutations in RMRP, encoding a non-coding RNA molecule, underlie cartilage-hair hypoplasia (CHH), a syndromic immunodeficiency with multiple pathogenetic mechanisms and variable phenotype. Allergy and asthma have been reported in the CHH population and some patients suffer from autoimmune (AI) diseases. Objective: We explored AI and allergic manifestations in a large cohort of Finnish patients with CHH and correlated clinical features with laboratory parameters and autoantibodies. Methods: We collected clinical and laboratory data from patient interviews and hospital records. Serum samples were tested for a range of autoantibodies including celiac, anti-cytokine, and anti-21-hydroxylase antibodies. Nasal cytology samples were analyzed with microscopy. Results: The study cohort included 104 patients with genetically confirmed CHH; their median age was 39.2 years (range 0.6-73.6). Clinical autoimmunity was common (11/104, 10.6%) and included conditions previously undescribed in subjects with CHH (narcolepsy, psoriasis, idiopathic thrombocytopenic purpura, and multifocal motor axonal neuropathy). Patients with autoimmunity more often had recurrent pneumonia, sepsis, high immunoglobulin (Ig) E and/or undetectable IgA levels. The mortality rates were higher in subjects with AI diseases (X-(2)(2) = 14.056, p = 0.0002). Several patients demonstrated serum autoantibody positivity without compatible symptoms. We confirmed the high prevalence of asthma (23%) and allergic rhinoconjunctivitis (39%). Gastrointestinal complaints, mostly persistent diarrhea, were also frequently reported (32/104, 31%). Despite the history of allergic rhinitis, no eosinophils were observed in nasal cytology in five tested patients. Conclusions: AI diseases are common in Finnish patients with CHH and are associated with higher mortality, recurrent pneumonia, sepsis, high IgE and/or undetectable IgA levels. Serum positivity for some autoantibodies was not associated with clinical autoimmunity. The high prevalence of persistent diarrhea, asthma, and symptoms of inflammation of nasal mucosa may indicate common pathways of immune dysregulation.
  • Koskinen, Lotta L. E.; Seppala, Eija H.; Weissl, Jutta; Jokinen, Tarja S.; Viitmaa, Ranno; Hanninen, Reetta L.; Quignon, Pascale; Fischer, Andrea; Andre, Catherine; Lohi, Hannes (2017)
    Background: Idiopathic or genetic adult-onset epilepsy is a common neurological disorder in domestic dogs. Genetic association has been reported only with ADAM23 on CFA 37 in few breeds. To identify novel epilepsy genes, we performed genome-wide association (GWA) analyses in four new breeds, and investigated the association of the previously reported ADAM23 haplotype with the epilepsy phenotype in eight breeds. Results: GWA analysis did not reveal new epilepsy loci. ADAM23 association (p <0.05) was identified in five breeds. Combined analysis of all eight breeds showed significant association (p = 4.6e(-6), OR 1.9). Conclusions: Our results further support the role of ADAM23 in multiple breeds as a common risk gene for epilepsy with low penetrance. The lack of findings in the GWA analyses points towards inefficient capture of genetic variation by the current SNP arrays, causal variant(s) with low penetrance and possible phenocopies. Future work will include studies on ADAM23 function and expression in canine neurons, as well as whole-genome sequencing in order to identify additional IE genes.
  • Llavona, Pablo; Pinelli, Michele; Mutarelli, Margherita; Singh Marwah, Veer; Schimpf-Linzenbold, Simone; Thaler, Sebastian; Yoeruek, Efdal; Vetter, Jan; Kohl, Susanne; Wissinger, Bernd (2017)
    Inherited retinal diseases (IRDs) are often associated with variable clinical expressivity (VE) and incomplete penetrance (IP). Underlying mechanisms may include environmental, epigenetic, and genetic factors. Cis-acting expression quantitative trait loci (cis-eQTLs) can be implicated in the regulation of genes by favoring or hampering the expression of one allele over the other. Thus, the presence of such loci elicits allelic expression imbalance (AEI) that can be traced by massive parallel sequencing techniques. In this study, we performed an AEI analysis on RNA-sequencing (RNA-seq) data, from 52 healthy retina donors, that identified 194 imbalanced single nucleotide polymorphisms(SNPs) in 67 IRD genes. Focusing on SNPs displaying AEI at a frequency higher than 10%, we found evidence of AEI in several IRD genes regularly associated with IP and VE (BEST1, RP1, PROM1, and PRPH2). Based on these SNPs commonly undergoing AEI, we performed pyrosequencing in an independent sample set of 17 healthy retina donors in order to confirm our findings. Indeed, we were able to validate CDHR1, BEST1, and PROM1 to be subjected to cis-acting regulation. With this work, we aim to shed light on differentially expressed alleles in the human retina transcriptome that, in the context of autosomal dominant IRD cases, could help to explain IP or VE.
  • Patel, V.L.; Busch, E.L.; Friebel, T.M.; Cronin, A.; Leslie, G.; McGuffog, L.; Adlard, J.; Agata, S.; Agnarsson, B.A.; Ahmed, M.; Aittomäki, K.; Alducci, E.; Andrulis, I.L.; Arason, A.; Arnold, N.; Artioli, G.; Arver, B.; Auber, B.; Azzollini, J.; Balmaña, J.; Barkardottir, R.B.; Barnes, D.R.; Barroso, A.; Barrowdale, D.; Belotti, M.; Benitez, J.; Bertelsen, B.; Blok, M.J.; Bodrogi, I.; Bonadona, V.; Bonanni, B.; Bondavalli, D.; Boonen, S.E.; Borde, J.; Borg, A.; Bradbury, A.R.; Brady, A.; Brewer, C.; Brunet, J.; Buecher, B.; Buys, S.S.; Cabezas-Camarero, S.; Caldes, T.; Caliebe, A.; Caligo, M.A.; Calvello, M.; Campbell, I.G.; Carnevali, I.; Carrasco, E.; Chan, T.L.; Chu, A.T.W.; Chung, W.K.; Claes, K.B.M.; Cook, J.; Cortesi, L.; Couch, F.J.; Daly, M.B.; Damante, G.; Darder, E.; Davidson, R.; De La Hoya, M.; Della Puppa, L.; Dennis, J.; Díez, O.; Ding, Y.C.; Ditsch, N.; Domchek, S.M.; Donaldson, A.; Dworniczak, B.; Easton, D.F.; Eccles, D.M.; Eeles, R.A.; Ehrencrona, H.; Ejlertsen, B.; Engel, C.; Evans, D.G.; Faivre, L.; Faust, U.; Feliubadalo, L.; Foretova, L.; Fostira, F.; Fountzilas, G.; Frost, D.; García-Barberan, V.; Garre, P.; Gauthier-Villars, M.; Geczi, L.; Gehrig, A.; Gerdes, A.-M.; Gesta, P.; Giannini, G.; Glendon, G.; Godwin, A.K.; Goldgar, D.E.; Greene, M.H.; Gutierrez-Barrera, A.M.; Hahnen, E.; Hamann, U.; Hauke, J.; Herold, N.; Hogervorst, F.B.L.; Honisch, E.; Hopper, J.L.; Hulick, P.J.; Izatt, L.; Jager, A.; James, P.; Janavicius, R.; Jensen, U.B.; Jensen, T.D.; Johannsson, O.Th.; John, E.M.; Joseph, V.; Kang, E.; Kast, K.; Kiiski, J.I.; Kim, S.-W.; Kim, Z.; Ko, K.-P.; Konstantopoulou, I.; Kramer, G.; Krogh, L.; Kruse, T.A.; Kwong, A.; Larsen, M.; Lasset, C.; Lautrup, C.; Lazaro, C.; Lee, J.; Lee, J.W.; Lee, M.H.; Lemke, J.; Lesueur, F.; Liljegren, A.; Lindblom, A.; Llovet, P.; Lopez-Fernandez, A.; Lopez-Perolio, I.; Lorca, V.; Loud, J.T.; Ma, E.S.K.; Mai, P.L.; Manoukian, S.; Mari, V.; Martin, L.; Matricardi, L.; Mebirouk, N.; Medici, V.; Meijers-Heijboer, H.E.J.; Meindl, A.; Mensenkamp, A.R.; Miller, C.; Gomes, D.M.; Montagna, M.; Mooij, T.M.; Moserle, L.; Mouret-Fourme, E.; Mulligan, A.M.; Nathanson, K.L.; Navratilova, M.; Nevanlinna, H.; Niederacher, D.; Cilius Nielsen, F.C.; Nikitina-Zake, L.; Offit, K.; Olah, E.; Olopade, O.I.; Ong, K.-R.; Osorio, A.; Ott, C.-E.; Palli, D.; Park, S.K.; Parsons, M.T.; Pedersen, I.S.; Peissel, B.; Peixoto, A.; Perez-Segura, P.; Peterlongo, P.; Petersen, A.H.; Porteous, M.E.; Pujana, M.A.; Radice, P.; Ramser, J.; Rantala, J.; Rashid, M.U.; Rhiem, K.; Rizzolo, P.; Robson, M.E.; Rookus, M.A.; Rossing, C.M.; Ruddy, K.J.; Santos, C.; Saule, C.; Scarpitta, R.; Schmutzler, R.K.; Schuster, H.; Senter, L.; Seynaeve, C.M.; Shah, P.D.; Sharma, P.; Shin, V.Y.; Silvestri, V.; Simard, J.; Singer, C.F.; Skytte, A.-B.; Snape, K.; Solano, A.R.; Soucy, P.; Southey, M.C.; Spurdle, A.B.; Steele, L.; Steinemann, D.; Stoppa-Lyonnet, D.; Stradella, A.; Sunde, L.; Sutter, C.; Tan, Y.Y.; Teixeira, M.R.; Teo, S.H.; Thomassen, M.; Tibiletti, M.G.; Tischkowitz, M.; Tognazzo, S.; Toland, A.E.; Tommasi, S.; Torres, D.; Toss, A.; Trainer, A.H.; Tung, N.; Van Asperen, C.J.; Van Der Baan, F.H.; Van Der Kolk, L.E.; Van Der Luijt, R.B.; Van Hest, L.P.; Varesco, L.; Varon-Mateeva, R.; Viel, A.; Vierstrate, J.; Villa, R.; Von Wachenfeldt, A.; Wagner, P.; Wang-Gohrke, S.; Wappenschmidt, B.; Weitzel, J.N.; Wieme, G.; Yadav, S.; Yannoukakos, D.; Yoon, S.-Y.; Zanzottera, C.; Zorn, K.K.; D’Amico, A.V.; Freedman, M.L.; Pomerantz, M.M.; Chenevix-Trench, G.; Antoniou, A.C.; Neuhausen, S.L.; Ottini, L.; Nielsen, H.R.; Rebbeck, T.R. (2020)
    Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
  • Twardziok, Monika; Schroder, Paul C.; Krusche, Johanna; Casaca, Vera I.; Illi, Sabina; Bock, Andreas; Loss, Georg J.; Kabesch, Michael; Toncheva, Antoaneta A.; Roduit, Caroline; Depner, Martin; Genuneit, Jon; Renz, Harald; Roponen, Marjut; Weber, Juliane; Braun-Fahrlander, Charlotte; Riedler, Josef; Lauener, Roger; Vuitton, Dominique Angele; Dalphin, Jean-Charles; Pekkanen, Juha; von Mutius, Erika; Schaub, Bianca; PASTURE Study Grp; Hyvarinen, Anne; Karvonen, Anne M.; Kirjavainen, Pirkka V.; Remes, Sami; Kaulek, Vincent; Dalphin, Marie-Laure; Ege, Markus; Pfefferle, Petra I.; Doekes, Gert (2017)
    Several studies report an important role of CD8(+) cytotoxic T-cells in atopy. Farm children show protection against atopy development, partly explained by CD4(+) T-cell subtypes. Additional effects of CD8(+) T-cells are unknown being investigated in this study within the PASTURE/EFRAIM birth cohort in PBMCs from farming and non-farming 6-year-old (N = 76) German children. CD3(+) CD8(+) CD25(+) T-cells were analyzed by flow cytometry. Genotyping of 17q21 locus-SNPs associated with childhood asthma was performed. No differences in CD8(+) T-cell subsets were seen between farmers and non-farmers regardless of asthma. Among farm children, asthmatics displayed increased CD3(+) CD8(low)(CD25(+)) T-cells compared to non-asthmatics. Asthmatic farm children exhibited a lower PI-induced stimulatory capacity of CD3(+) CD8(low)(CD25(+)) cells and a lower IFN-gamma secretion than non-asthmatic farm children. Among farm children with GSDMB and ORMDL3 risk alleles, asthmatics displayed higher CD3(+) CD8(low) cells than non-asthmatics. Our data indicates a specific role of CD8(low) T-cells in asthmatic farm children. (C) 2017 Elsevier Inc. All rights reserved.
  • Garcia-Romero, Noemi; Gonzalez-Tejedo, Carmen; Carrion-Navarro, Josefa; Esteban-Rubio, Susana; Rackov, Gorjana; Rodriguez-Fanjul, Vanessa; Oliver-De La Cruz, Jorge; Prat-Acin, Ricardo; Peris-Celda, Maria; Blesa, David; Ramirez-Jimenez, Laura; Sanchez-Gomez, Pilar; Perona, Rosario; Escobedo-Lucea, Carmen; Belda-Iniesta, Cristobal; Ayuso-Sacido, Angel (2016)
    Human gliomas harbour cancer stem cells (CSCs) that evolve along the course of the disease, forming highly heterogeneous subpopulations within the tumour mass. These cells possess self-renewal properties and appear to contribute to tumour initiation, metastasis and resistance to therapy. CSC cultures isolated from surgical samples are considered the best preclinical in vitro model for primary human gliomas. However, it is not yet well characterized to which extent their biological and functional properties change during in vitro passaging in the serum-free culture conditions. Here, we demonstrate that our CSC-enriched cultures harboured from one to several CSC clones from the human glioma sample. When xenotransplanted into mouse brain, these cells generated tumours that reproduced at least three different dissemination patterns found in original tumours. Along the passages in culture, CSCs displayed increased expression of stem cell markers, different ratios of chromosomal instability events, and a varied response to drug treatment. Our findings highlight the need for better characterization of CSC-enriched cultures in the context of their evolution in vitro, in order to uncover their full potential as preclinical models in the studies aimed at identifying molecular biomarkers and developing new therapeutic approaches of human gliomas.
  • Eichin, Dominik; Pessia, Alberto; Takeda, Akira; Laakkonen, Joni; Bellmann, Lydia; Kankainen, Matti; Imhof, Beat A.; Stoitzner, Patrizia; Tang, Jing; Salmi, Marko; Jalkanen, Sirpa (2021)
    CD73 is an important ectoenzyme responsible for the production of extracellular adenosine. It is involved in regulating inflammatory responses and cell migration and is overexpressed in various cancers. The functions of CD73 in blood endothelial cells are understood in detail, but its role on afferent lymphatics remains unknown. Moreover, anti‐CD73 antibodies are now used in multiple clinical cancer trials, but their effects on different endothelial cell types have not been studied. This study reveals that a previously unknown role of CD73 on afferent lymphatics is to dampen immune responses. Knocking it out or suppressing it by siRNA leads to the upregulation of inflammation‐associated genes on lymphatic endothelial cells and a more pro‐inflammatory phenotype of interacting dendritic cells in vitro and in vivo. In striking contrast, anti‐CD73 antibodies had only negligible effects on the gene expression of lymphatic‐ and blood‐endothelial cells. Our data thus reveal new functions of lymphatic CD73 and indicate a low likelihood of endothelial cell–related adverse effects by CD73 targeting therapeutic antibodies.
  • Hagolani, Pascal F.; Zimm, Roland; Marin-Riera, Miquel; Salazar-Ciudad, Isaac (2019)
    Embryonic development involves gene networks, extracellular signaling, cell behaviors (cell division, adhesion, etc.) and mechanical interactions. How should these be coordinated to lead to complex and robust morphologies? To explore this question, we randomly wired genes and cell behaviors into a huge number of networks in EmbryoMaker. EmbryoMaker is a computational model of animal development that simulates how the 3D positions of cells, i.e. morphology, change over time due to such networks. We found that any gene network can lead to complex morphologies if this activates cell behaviors over large regions of the embryo. Importantly, however, for such complex morphologies to be robust to noise, gene networks should include cell signaling that compartmentalizes the embryo into small regions where cell behaviors are regulated differently. If, instead, cell behaviors are equally regulated over large regions, complex but non-robust morphologies arise. We explain how compartmentalization enhances robustness and why it is a general feature of animal development. Our results are consistent with theories proposing that robustness evolved by the co-option of gene networks and extracellular cell signaling in early animal evolution.
  • Gaudet, Mia M.; Kirchhoff, Tomas; Green, Todd; Vijai, Joseph; Korn, Joshua M.; Guiducci, Candace; Segre, Ayellet V.; McGee, Kate; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Gauthier-Villars, Marion; Sobol, Hagay; Longy, Michel; Frenay, Marc; Hogervorst, Frans B. L.; Rookus, Matti A.; Collee, J. Margriet; Hoogerbrugge, Nicoline; van Roozendaal, Kees E. P.; Piedmonte, Marion; Rubinstein, Wendy; Nerenstone, Stacy; Van Le, Linda; Blank, Stephanie V.; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.; Devilee, Peter; Olopade, Olofunmilayo I.; Neuhausen, Susan L.; Wang, Xianshu; Fredericksen, Zachary S.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Viel, Alessandra; Radice, Paolo; Phelan, Catherine M.; Narod, Steven; kConFab, OCGN, HEBON Study Collaborators, GEMO Study Collaborators (2010)
  • Maguire, Sarah; Perraki, Eleni; Tomczyk, Katarzyna; KConFab Consortium; Trainer, Alison; James, Paul; Bojesen, Stig; Flyger, Henrik; Nevanlinna, Heli; Mattson, Johanna; Friedman, Eital; Laitman, Yael; Palli, Domenico; Masala, Giovanna; Zanna, Ines; Ottini, Laura; Silvestri, Valentina; Hollestelle, Antoinette; Hooning, Maartje J.; Novakovic, Srdjan; Krajc, Mateja; Gago-Dominguez, Manuela; Castelao, Jose Esteban; Olsson, Hakan; Hedenfalk, Ingrid; Saloustros, Emmanouil; Georgoulias, Vasilios; Easton, Douglas F.; Pharoah, Paul; Dunning, Alison M.; Bishop, D. Timothy; Neuhausen, Susan L.; Steele, Linda; Ashworth, Alan; Garcia Closas, Montserrat; Houlston, Richard; Swerdlow, Anthony; Orr, Nick (2021)
    Background: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. Methods: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 x 10(-06). Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. Results: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 x 10(-08)). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 x 10(-30)). Conclusions: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.
  • Gursoy, Ulvi K.; Gursoy, Mervi; Kononen, Eija; Sintim, Herman O.; Uitto, Veli-Jukka; Syrjanen, Stina (2016)
    In construction of epithelial cells as multilayers, the cells are grown submerged to confluence on fibroblast-embedded collagen gels and, then, lifted to air to promote their stratification. We recently demonstrated that gingival epithelial cells form uniform monolayers on semi-permeable nitrocellulose membranes, supported with a semi-solid growth medium, which allows the cells to grow at an air-liquid-solid interface from the beginning of the culturing protocol. In this study, the aim was to further develop our previous model to form a multilayered gingival epithelial culture model. Two different epithelial cell lines (HaCaT from skin and HMK from gingiva) were used in all experiments. Both cell lines were grown first as monolayers for 3 days. After that, keratinocytes were trypsinized, counted and seeded on a sterile semi-permeable nitrocellulose membrane placed on the top of a semi-solid growth medium, forming an air-liquid-solid interface for the cells to grow. At days 1, 4, and 7, epithelial cells were fixed, embedded in paraffin, and sectioned for routine Hematoxylin-Eosin staining and immunohistochemistry for cytokeratin (Ck). At day 1, HMK cells grew as monolayers, while HaCaT cells stratified forming an epithelium with two to three layers. At day 4, a stratified epithelium in the HMK model had four to five layers and its proliferation continued up to day 7. HaCaT cells formed a dense and weakly proliferating epithelium with three to four layers of stratification at day 4 but the proliferation disappeared at day 7. At all days, both models were strongly positive for Ck5, Ck7, and Ck 19, and weakly positive for Ck10. Gingival epithelial cells stratify successfully on semi-permeable nitrocellulose membranes, supported with a semi-solid growth medium. This technique allows researchers to construct uniform gingival epithelial cell multilayers at an air-liquid-solid interface, without using collagen gels, resulting in a more reproducible method.
  • Apu, Ehsanul Hoque; Akram, Saad Ullah; Rissanen, Jouni; Wan, Hong; Salo, Tuula (2018)
    Desmoglein 3 (Dsg3) is an adhesion receptor in desmosomes, but its role in carcinoma cell migration and invasion is mostly unknown. Our aim was to quantitatively analyse the motion of Dsg3-modified carcinoma cells in 2D settings and in 3D within tumour microenvironment mimicking (TMEM) matrices. We tested mutant constructs of C-terminally truncated Dsg3 (Delta 238 and Delta 560), overexpressed full-length (FL) Dsg3, and empty vector control (Ct) of buccal mucosa squamous cell carcinoma (SqCC/Y1) cells. We captured live cell images and analysed migration velocities and accumulated and Euclidean distances. We compared rodent collagen and Matrigel. with human Myogel TMEM matrices for these parameters in 3D sandwich, in which we also tested the effects of monoclonal antibody AK23, which targets the EC1 domain of Dsg3. In monolayer culture, FL and both truncated constructs migrated faster and had higher accumulated distances than Ct cells. However, in the 3D assays, only the mutants invaded faster relative to Ct cells. Of the mutants, the shorter form (Delta 238) exhibited faster migration and invasion than Delta 560 cells. In the Transwell, all of the cells invaded faster through Myogel than Matrigel coated wells. In 3D sandwich, AK23 antibody inhibited only the invasion of FL cells. We conclude that different experimental 2D and 3D settings can markedly influence the movement of oral carcinoma cells with various Dsg3 modifications.
  • EuroEPINOMICS- RES Consortium; EpiCNV Consortium; Coppola, Antonietta; Cellini, Elena; Saarentaus, Elmo; Palotie, Aarno; Lehesjioki, Anna-Elina; von Spiczak, Sarah (2019)
    Objective Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 x 10(-9)). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.
  • Blatter, Robert; Tschupp, Benjamin; Aretz, Stefan; Bernstein, Inge; Colas, Chrystelle; Evans, D. Gareth; Genuardi, Maurizio; Hes, Frederik J.; Hueneburg, Robert; Jarvinen, Heikki; Lalloo, Fiona; Moeslein, Gabriela; Renkonen-Sinisalo, Laura; Resta, Nicoletta; Spier, Isabel; Varvara, Dora; Vasen, Hans; Latchford, Andrew R.; Heinimann, Karl (2020)
    Purpose Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. Methods We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. Results We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). Conclusion This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.