Browsing by Subject "GENES"

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  • 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.
  • Rantala, Juha K.; Makela, Rami; Aaltola, Anna-Riina; Laasola, Petra; Mpindi, John-Patrick; Nees, Matthias; Saviranta, Petri; Kallioniemi, Olli (2011)
  • Prokopenko, Inga; Poon, Wenny; Maegi, Reedik; Prasad, Rashmi B.; Salehi, S. Albert; Almgren, Peter; Osmark, Peter; Bouatia-Naji, Nabila; Wierup, Nils; Fall, Tove; Stancakova, Alena; Barker, Adam; Lagou, Vasiliki; Osmond, Clive; Xie, Weijia; Lahti, Jari; Jackson, Anne U.; Cheng, Yu-Ching; Liu, Jie; O'Connell, Jeffrey R.; Blomstedt, Paul A.; Fadista, Joao; Alkayyali, Sami; Dayeh, Tasnim; Ahlqvist, Emma; Taneera, Jalal; Lecoeur, Cecile; Kumar, Ashish; Hansson, Ola; Hansson, Karin; Voight, Benjamin F.; Kang, Hyun Min; Levy-Marchal, Claire; Vatin, Vincent; Palotie, Aarno; Syvanen, Ann-Christine; Mari, Andrea; Weedon, Michael N.; Loos, Ruth J. F.; Ong, Ken K.; Nilsson, Peter; Isomaa, Bo; Tuomi, Tiinamaija; Wareham, Nicholas J.; Stumvoll, Michael; Widen, Elisabeth; Lakka, Timo A.; Langenberg, Claudia; Tonjes, Anke; Rauramaa, Rainer; Kuusisto, Johanna; Frayling, Timothy M.; Froguel, Philippe; Walker, Mark; Eriksson, Johan G.; Ling, Charlotte; Kovacs, Peter; Ingelsson, Erik; McCarthy, Mark I.; Shuldiner, Alan R.; Silver, Kristi D.; Laakso, Markku; Groop, Leif; Lyssenko, Valeriya (2014)
  • Radhakrishnan, Dhanya; Shanmukhan, Anju Pallipurath; Kareem, Abdul; Aiyaz, Mohammed; Varapparambathu, Vijina; Toms, Ashna; Kerstens, Merijn; Valsakumar, Devisree; Landge, Amit N.; Shaji, Anil; Mathew, Mathew K.; Sawchuk, Megan G.; Scarpella, Enrico; Krizek, Beth A.; Efroni, Idan; Mähönen, Ari Pekka; Willemsen, Viola; Scheres, Ben; Prasad, Kalika (2020)
    Aerial organs of plants, being highly prone to local injuries, require tissue restoration to ensure their survival. However, knowledge of the underlying mechanism is sparse. In this study, we mimicked natural injuries in growing leaves and stems to study the reunion between mechanically disconnected tissues. We show that PLETHORA (PLT) and AINTEGUMENTA (ANT) genes, which encode stem cell-promoting factors, are activated and contribute to vascular regeneration in response to these injuries. PLT proteins bind to and activate the CUC2 promoter. PLT proteins and CUC2 regulate the transcription of the local auxin biosynthesis gene YUC4 in a coherent feed-forward loop, and this process is necessary to drive vascular regeneration. In the absence of this PLT-mediated regeneration response, leaf ground tissue cells can neither acquire the early vascular identity marker ATHB8, nor properly polarise auxin transporters to specify new venation paths. The PLT-CUC2 module is required for vascular regeneration, but is dispensable for midvein formation in leaves. We reveal the mechanisms of vascular regeneration in plants and distinguish between the wound-repair ability of the tissue and its formation during normal development.
  • Darragh, Kathy; Orteu, Anna; Black, Daniella; Byers, Kelsey J. R. P.; Szczerbowski, Daiane; Warren, Ian A.; Rastas, Pasi; Pinharanda, Ana; Davey, John W.; Fernanda Garza, Sylvia; Abondano Almeida, Diana; Merrill, Richard M.; McMillan, W. Owen; Schulz, Stefan; Jiggins, Chris D. (2021)
    Plants and insects often use the same compounds for chemical communication, but not much is known about the genetics of convergent evolution of chemical signals. The terpene (E)-beta-ocimene is a common component of floral scent and is also used by the butterfly Heliconius melpomene as an anti-aphrodisiac pheromone. While the biosynthesis of terpenes has been described in plants and microorganisms, few terpene synthases (TPSs) have been identified in insects. Here, we study the recent divergence of 2 species, H. melpomene and Heliconius cydno, which differ in the presence of (E)-beta-ocimene; combining linkage mapping, gene expression, and functional analyses, we identify 2 novel TPSs. Furthermore, we demonstrate that one, HmelOS, is able to synthesise (E)-beta-ocimene in vitro. We find no evidence for TPS activity in HcydOS (HmelOS ortholog of H. cydno), suggesting that the loss of (E)-beta-ocimene in this species is the result of coding, not regulatory, differences. The TPS enzymes we discovered are unrelated to previously described plant and insect TPSs, demonstrating that chemical convergence has independent evolutionary origins.
  • Oamen, Henry Patrick; Romero, Nathaly Romero; Knuckles, Philip; Saarikangas, Juha; Radman-Livaja, Marta; Dong, Yuhong; Caudron, Fabrice (2022)
    Most neurodegenerative diseases such as Alzheimer's disease are proteinopathies linked to the toxicity of amyloid oligomers. Treatments to delay or cure these diseases are lacking. Using budding yeast, we report that the natural lipid tripentadecanoin induces expression of the nitric oxide oxidoreductase Yhb1 to prevent the formation of protein aggregates during aging and extends replicative lifespan. In mammals, tripentadecanoin induces expression of the Yhb1 orthologue, neuroglobin, to protect neurons against amyloid toxicity. Tripentadecanoin also rescues photoreceptors in a mouse model of retinal degeneration and retinal ganglion cells in a Rhesus monkey model of optic atrophy. Together, we propose that tripentadecanoin affects p-bodies to induce neuroglobin expression and offers a potential treatment for proteinopathies and retinal neurodegeneration.
  • Savarese, Marco; Palmio, Johanna; Poza, Juan Jose; Weinberg, Jan; Olive, Montse; Cobo, Ana Maria; Vihola, Anna; Jonson, Per Harald; Sarparanta, Jaakko; Garcia-Bragado, Federico; Urtizberea, Jon Andoni; Hackman, Peter; Udd, Bjarne (2019)
    Objective To clinically and pathologically characterize a cohort of patients presenting with a novel form of distal myopathy and to identify the genetic cause of this new muscular dystrophy. Methods We studied 4 families (3 from Spain and 1 from Sweden) suffering from an autosomal dominant distal myopathy. Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles. Results In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease. The affected members of the Swedish family carry a different ACTN2 missense variant. Interpretation ACTN2 encodes for alpha actinin2, which is highly expressed in the sarcomeric Z-disk with a major structural and functional role. Actininopathy is thus a new genetically determined distal myopathy. ANN NEUROL 2019;85:899-906.
  • Luyten, Walter; Antal, Peter; Braeckman, Bart P.; Bundy, Jake; Cirulli, Francesca; Fang-Yen, Christopher; Fuellen, Georg; Leroi, Armand; Liu, Qingfei; Martorell, Patricia; Metspalu, Andres; Perola, Markus; Ristow, Michael; Saul, Nadine; Schoofs, Liliane; Siems, Karsten; Temmerman, Liesbet; Smets, Tina; Wolk, Alicja; Rattan, Suresh I. S. (2016)
    Human longevity continues to increase world-wide, often accompanied by decreasing birth rates. As a larger fraction of the population thus gets older, the number of people suffering from disease or disability increases dramatically, presenting a major societal challenge. Healthy ageing has therefore been selected by EU policy makers as an important priority ; it benefits not only the elderly but also their direct environment and broader society, as well as the economy. The theme of healthy ageing figures prominently in the Horizon 2020 programme , which has launched several research and innovation actions (RIA), like "Understanding health, ageing and disease: determinants, risk factors and pathways" in the work programme on "Personalising healthcare". Here we present our research proposal entitled "ageing with elegans" (AwE), funded by this RIA, which aims for better understanding of the factors causing health and disease in ageing, and to develop evidence-based prevention, diagnostic, therapeutic and other strategies. The aim of this article, authored by the principal investigators of the 17 collaborating teams, is to describe briefly the rationale, aims, strategies and work packages of AwE for the purposes of sharing our ideas and plans with the biogerontological community in order to invite scientific feedback, suggestions, and criticism.
  • PanScan PanC4 consortia; Walsh, Naomi; Zhang, Han; Männistö, Satu; Weiderpass, Elisabete (2019)
    Background Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P Conclusion Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
  • Liu, Mengxia; Wang, Kai; Haapanen, Matti; Ghimire, Rajendra P. P.; Kivimaenpaa, Minna; Asiegbu, Fred O. O. (2022)
    Root and stem rot caused by Heterobasidion annosum is a severe problem in boreal Scots pine. Dissecting the features of disease resistance is generally an essential step in resistance breeding in plants and forest trees. In this study, we explored inherent resistance factors of Scots pine against H. annosum. A total of 236 families consisting of 85 full-sib (FS), 35 half-sib population mix (HSpm), and 116 half-sib (HS) families of Scots pine seedlings were inoculated with a H. annosum isolate. We sampled needle tissues before inoculation for terpene measurements and RNA sequencing. Based on the lesion area, the extremes of 12 resistant and 12 susceptible families were selected for further analyses. Necrotic lesions resulting from fungal infection were in a weak to moderate relationship with the plant height. Monoterpenes were the principal terpene compounds observed in Scots pine seedlings. Concentrations of 3-carene were significantly higher in pine genotypes inherently resistant compared with susceptible seedlings. By contrast, susceptible genotypes had significantly higher proportions of alpha-pinene. Gene ontology analysis of differential expressed transcripts (DETs) revealed that response to biotic factors was enriched in resistant seedlings. Functional characterization of individual DETs revealed that higher expression of transcripts involved in response to abiotic stress was common in susceptible genotypes. This observation was supported by the annotation of hub genes in a key module that was significantly correlated with the lesion trait through weighted gene co-expression network analysis (WGCNA) of 16 HS and HSpm samples. These findings contribute to our understanding of constitutive resistance factors of Scots pine against Heterobasidion root and stem rot diseases.
  • Parnanen, Katariina M. M.; Narciso-da-Rocha, Carlos; Kneis, David; Berendonk, Thomas U.; Cacace, Damiano; Do, Thi Thuy; Elpers, Christian; Fatta-Kassinos, Despo; Henriques, Isabel; Jaeger, Thomas; Karkman, Antti; Luis Martinez, Jose; Michael, Stella G.; Michael-Kordatou, Irene; O'Sullivan, Kristin; Rodriguez-Mozaz, Sara; Schwartz, Thomas; Sheng, Hongjie; Sorum, Henning; Stedtfeld, Robert D.; Tiedje, James M.; Varela Della Giustina, Saulo; Walsh, Fiona; Vaz-Moreira, Ivone; Virta, Marko; Manaia, Celia M. (2019)
    Integrated antibiotic resistance (AR) surveillance is one of the objectives of the World Health Organization global action plan on antimicrobial resistance. Urban wastewater treatment plants (UWTPs) are among the most important receptors and sources of environmental AR. On the basis of the consistent observation of an increasing north-to-south clinical AR prevalence in Europe, this study compared the influent and final effluent of 12 UWTPs located in seven countries (Portugal, Spain, Ireland, Cyprus, Germany, Finland, and Norway). Using highly parallel quantitative polymerase chain reaction, we analyzed 229 resistance genes and 25 mobile genetic elements. This first trans-Europe surveillance showed that UWTP AR profiles mirror the AR gradient observed in clinics. Antibiotic use, environmental temperature, and UWTP size were important factors related with resistance persistence and spread in the environment. These results highlight the need to implement regular surveillance and control measures, which may need to be appropriate for the geographic regions.
  • Hiltunen, Teppo; Virta, Marko; Laine, Anna-Liisa (2017)
    The legacy of the use and misuse of antibiotics in recent decades has left us with a global public health crisis: antibiotic-resistant bacteria are on the rise, making it harder to treat infections. At the same time, evolution of antibiotic resistance is probably the best-documented case of contemporary evolution. To date, research on antibiotic resistance has largely ignored the complexity of interactions that bacteria engage in. However, in natural populations, bacteria interact with other species; for example, competition and grazing are import interactions influencing bacterial population dynamics. Furthermore, antibiotic leakage to natural environments can radically alter bacterial communities. Overall, we argue that eco-evolutionary feedback loops in microbial communities can be modified by residual antibiotics and evolution of antibiotic resistance. The aim of this review is to connect some of the well-established key concepts in evolutionary biology and recent advances in the study of eco-evolutionary dynamics to research on antibiotic resistance. We also identify some key knowledge gaps related to eco-evolutionary dynamics of antibiotic resistance, and review some of the recent technical advantages in molecular microbiology that offer new opportunities for tackling these questions. Finally, we argue that using the full potential of evolutionary theory and active communication across the different fields is needed for solving this global crisis more efficiently. This article is part of the themed issue 'Human influences on evolution, and the ecological and societal consequences'.
  • Topp, Edward; Larsson, D. G. Joakim; Miller, Daniel N.; Van den Eede, Chris; Virta, Marko P. J. (2018)
    A roundtable discussion held at the fourth International Symposium on the Environmental Dimension of Antibiotic Resistance (EDAR4) considered key issues concerning the impact on the environment of antibiotic use in agriculture and aquaculture, and emissions from antibiotic manufacturing. The critical control points for reducing emissions of antibiotics from agriculture are antibiotic stewardship and the pre-treatment of manure and sludge to abate antibiotic-resistant bacteria. Antibiotics are sometimes added to fish and shellfish production sites via the feed, representing a direct route of contamination of the aquatic environment. Vaccination reduces the need for antibiotic use in high value (e.g. salmon) production systems. Consumer and regulatory pressure will over time contribute to reducing the emission of very high concentrations of antibiotics from manufacturing. Research priorities include the development of technologies, practices and incentives that will allow effective reduction in antibiotic use, together with evidence-based standards for antibiotic residues in effluents. All relevant stakeholders need to be aware of the threat of antimicrobial resistance and apply best practice in agriculture, aquaculture and pharmaceutical manufacturing in order to mitigate antibiotic resistance development. Research and policy development on antimicrobial resistance mitigation must be cognizant of the varied challenges facing high and low income countries.
  • kConFab Investigators; HEBON Investigators; SWE BRCA Investigators; Muranen, Taru A.; Khan, Sofia; Fagerholm, Rainer; Aittomäki, Kristiina; Cunningham, Julie M.; Blomqvist, Carl; Nevanlinna, Heli (2020)
    Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P=3.1x10(-9)). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.
  • van der Knoop, Marieke M.; Maroofian, Reza; Fukata, Yuko; van Ierland, Yvette; Karimiani, Ehsan G.; Lehesjoki, Anna Elina; Muona, Mikko; Paetau, Anders; Miyazaki, Yuri; Hirano, Yoko; Selim, Laila; de Franca, Marina; Fock, Rodrigo Ambrosio; Beetz, Christian; Ruivenkamp, Claudia A. L.; Eaton, Alison J.; Morneau-Jacob, Francois D.; Sagi-Dain, Lena; Shemer-Meiri, Lilach; Peleg, Amir; Haddad-Halloun, Jumana; Kamphuis, Daan J.; Peeters-Scholte, Cacha M. P. C. D.; Kurul, Semra Hiz; Horvath, Rita; Lochmueller, Hanns; Murphy, David; Waldmueller, Stephan; Spranger, Stephanie; Overberg, David; Muir, Alison M.; Rad, Aboulfazl; Vona, Barbara; Abdulwahad, Firdous; Maddirevula, Sateesh; Povolotskaya, Inna S.; Voinova, Victoria Y.; Gowda, Vykuntaraju K.; Srinivasan, Varunvenkat M.; Alkuraya, Fowzan S.; Mefford, Heather C.; Alfadhel, Majid; Haack, Tobias B.; Striano, Pasquale; Severino, Mariasavina; Fukata, Masaki; Hilhorst-Hofstee, Yvonne; Houlden, Henry (2022)
    Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Van der Knoop et al. describe the clinical features of 21 individuals with biallelic pathogenic variants in ADAM22 and confirm the deleteriousness of the variants with functional studies. Clinical hallmarks of this rare disorder comprise progressive encephalopathy and infantile-onset refractory epilepsy.
  • Hytönen, Marjo K.; Arumilli, Meharji; Sarkiala, Eva; Nieminen, Pekka; Lohi, Hannes (2019)
    Amelogenesis imperfecta (AI) refers to a genetically and clinically heterogeneous group of inherited disorders affecting the structure, composition, and quantity of tooth enamel. Both non-syndromic and syndromic forms of AI have been described and several genes affecting various aspects of the enamel physiology have been reported. Genetically modified murine models of various genes have provided insights into the complex regulation of proper amelogenesis. Non-syndromic AI occurs spontaneously also in dogs with known recessive variants in ENAM and SLC24A4 genes. Unlike rodents with a reduced dentition and continuously erupting incisors, canine models are valuable for human AI due to similarity in the dental anatomy including deciduous and permanent teeth. We have performed a series of clinical and genetic analyses to investigate AI in several breeds of dogs and describe here two novel recessive variants in the ENAM and ACP4 genes. A fully segregating missense variant (c.716C>T) in exon 8 of ENAM substitutes a well-conserved proline to leucine, p.(Pro239Leu), resulting in a clinical hypomineralization of teeth. A 1-bp insertion in ACP4 (c.1189dupG) is predicted to lead to a frameshift, p.(Ala397Glyfs), resulting in an abnormal C-terminal part of the protein, and hypoplastic AI. The ENAM variant was specific for Parson Russell Terriers with a carrier frequency of 9%. The ACP4 variant was found in two breeds, Akita and American Akita with a carrier frequency of 22%. These genetic findings establish novel canine models of human AI with a particular interest in the case of the ACP4-deficient model, since ACP4 physiology is poorly characterized in human AI. The affected dogs could also serve as preclinical models for novel treatments while the breeds would benefit from genetic tests devised here for veterinary diagnostics and breeding programs.
  • Tukiainen, Taru; Pirinen, Matti; Sarin, Antti-Pekka; Ladenvall, Claes; Kettunen, Johannes; Lehtimaeki, Terho; Lokki, Marja-Liisa; Perola, Markus; Sinisalo, Juha; Vlachopoulou, Efthymia; Eriksson, Johan G.; Groop, Leif; Jula, Antti; Jaervelin, Marjo-Riitta; Raitakari, Olli T.; Salomaa, Veikko; Ripatti, Samuli (2014)
  • Lubbers, Ronnie J. M.; Dilokpimol, Adiphol; Navarro, Jorge; Peng, Mao; Wang, Mei; Lipzen, Anna; Ng, Vivian; Grigoriev, Igor V.; Visser, Jaap; Hildén, Kristiina S.; de Vries, Ronald P. (2019)
    Cinnamic acid is an aromatic compound commonly found in plants and functions as a central intermediate in lignin synthesis. Filamentous fungi are able to degrade cinnamic acid through multiple metabolic pathways. One of the best studied pathways is the non-oxidative decarboxylation of cinnamic acid to styrene. In Aspergillus niger, the enzymes cinnamic acid decarboxylase (CdcA, formally ferulic acid decarboxylase) and the flavin prenyltransferase (PadA) catalyze together the non-oxidative decarboxylation of cinnamic acid and sorbic acid. The corresponding genes, cdcA and padA, are clustered in the genome together with a putative transcription factor previously named sorbic acid decarboxylase regulator (SdrA). While SdrA was predicted to be involved in the regulation of the non-oxidative decarboxylation of cinnamic acid and sorbic acid, this was never functionally analyzed. In this study, A. niger deletion mutants of sdrA, cdcA, and padA were made to further investigate the role of SdrA in cinnamic acid metabolism. Phenotypic analysis revealed that cdcA, sdrA and padA are exclusively involved in the degradation of cinnamic acid and sorbic acid and not required for other related aromatic compounds. Whole genome transcriptome analysis of ΔsdrA grown on different cinnamic acid related compounds, revealed additional target genes, which were also clustered with cdcA, sdrA, and padA in the A. niger genome. Synteny analysis using 30 Aspergillus genomes demonstrated a conserved cinnamic acid decarboxylation gene cluster in most Aspergilli of the Nigri clade. Aspergilli lacking certain genes in the cluster were unable to grow on cinnamic acid, but could still grow on related aromatic compounds, confirming the specific role of these three genes for cinnamic acid metabolism of A. niger.
  • Murata, Tomohiro; Katayama, Kan; Oohashi, Toshitaka; Jahnukainen, Timo; Yonezawa, Tomoko; Sado, Yoshikazu; Ishikawa, Eiji; Nomura, Shinsuke; Tryggvason, Karl; Ito, Masaaki (2016)
    Alport syndrome is caused by mutations in the genes encoding alpha 3, alpha 4, or alpha 5 (IV) chains. Unlike X-linked Alport mice, alpha 5 and alpha 6 (IV) chains are detected in the glomerular basement membrane of autosomal recessive Alport mice, however, the significance of this finding remains to be investigated. We therefore generated mice lacking both alpha 3 and alpha 6 (IV) chains and compared their renal function and survival with Col4a3 knockout mice of 129 x 1/Sv background. No significant difference was observed in the renal function or survival of the two groups, or when the mice were backcrossed once to C57BL/6 background. However, the survival of backcrossed double knockout mice was significantly longer than that of the mice of 129 x 1/Sv background, which suggests that other modifier genes were involved in this phenomenon. In further studies we identified two Alport patients who had a homozygous mutation in intron 46 of COL4A4. The alpha 5 and alpha 6 (IV) chains were focally detected in the glomerular basement membrane of these patients. These findings indicate that although a5 and a6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role.