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| Open AccessBiallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity
Primary immunodeficiency disorders can be used to identify key immune functions. Here, the authors identify a biallelic mutation in the gene encoding NF-κB-inducing kinase in a family suffering a range of infections, and show that it causes defects in NK and T-cell function and has broad effects on B-cell function.
- Katharina L. Willmann
- , Stefanie Klaver
- & Kaan Boztuğ
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Evolutionary triage governs fitness in driver and passenger mutations and suggests targeting never mutations
The accumulation of genetic and epigenetic mutations in cancer cells can drive malignant growth. Here, the authors model the evolution of intratumoral diversity and examine the classification of driver and passenger mutations, heterogeneity within tumours, and the dynamics of tumour response to targeted therapies.
- R. A. Gatenby
- , J. J. Cunningham
- & J. S. Brown
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Decreased tumorigenesis in mice with a Kras point mutation at C118
The Ras family of proteins is frequently mutated in cancer, and free radical oxidants can also activate these proteins via modifications at cysteine 118 (C118). Here the authors introduce a C118S mutant Krasgene into mice and show that this mutant allele results in a reduction in lung tumorigenesis.
- Lu Huang
- , John Carney
- & Christopher M. Counter
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Crystal structures of wild type and disease mutant forms of the ryanodine receptor SPRY2 domain
Ryanodine receptors (RyRs) are endoplasmic and sarcoplasmic reticulum calcium channels. Here Lau et al.solve the structure of the SPRY2 domain from skeletal muscle RyR1, locate it within full-length RyR1 and show that a disease-causing mutation destabilizes the domain.
- Kelvin Lau
- & Filip Van Petegem
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Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in young adults. Here, the authors show that mutations in a sarcomeric protein filamin C contribute to the development of familial HCM and are associated with an increased incidence of sudden cardiac death.
- Rafael Valdés-Mas
- , Ana Gutiérrez-Fernández
- & Carlos López-Otín
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Article
| Open AccessIncreasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations
Mutations in the kinase LRRK2 are associated with Parkinson’s disease. Godena et al. find that disease-associated LRRK2 mutations promote its binding to deacetylated microtubules, and cause defects in axonal transport and Drosophilalocomotor behaviour that can be reversed by enhancing tubulin acetylation.
- Vinay K. Godena
- , Nicholas Brookes-Hocking
- & Kurt J. De Vos
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Activation of diverse signalling pathways by oncogenic PIK3CA mutations
Mutations in PIK3CA, a catalytic subunit of PI3 kinase, are linked to deregulation of Akt-mTOR signalling in many cancers. Here, using a SILAC-based quantitative proteomic approach, the authors discover six new AKT1 substrates, including the actin regulator cortactin.
- Xinyan Wu
- , Santosh Renuse
- & Akhilesh Pandey
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Phenotypic characterization of missense polymerase-δ mutations using an inducible protein-replacement system
The essential nature of replicative polymerases has hampered the study of polymerase-δ mutations found in colorectal cancer cells. Here, using polymerase-δ mutations as a proof of principle, the authors present an inducible single vector system that replaces any endogenous gene with an RNAi-resistant mutant version.
- Medini Manohar Ghodgaonkar
- , Patrick Kehl
- & Josef Jiricny
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An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry
Abnormal accumulation of the RNA-binding protein FUS and mutations within the FUS gene have been found in association with amyotrophic lateral sclerosis (ALS). Here, Dini Modigliani et al.uncover a FUS regulatory circuit that implicates the microRNAs miR-141 and miR-200a in a feedback loop disrupted by an ALS-associated mutation.
- Stefano Dini Modigliani
- , Mariangela Morlando
- & Irene Bozzoni
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A mutation burst during the acute phase of Helicobacter pylori infection in humans and rhesus macaques
Helicobacter pylori chronically infects humans, and this is associated with high mutation and recombination rates in the bacterium. Here the authors provide evidence that genome evolution in H. pyloriduring acute infection of the host is orders of magnitude faster than any previously determined mutation rates in bacteria.
- Bodo Linz
- , Helen M. Windsor
- & Barry J. Marshall
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Adaptive synonymous mutations in an experimentally evolved Pseudomonas fluorescens population
Synonymous mutations, nucleotide changes that do not alter the encoded amino acid, are usually seen not to have an effect on organism survival. Here, Bailey et al. show that two synonymous mutations in Pseudomonas fluorescenshad a beneficial effect and acted via increased gene expression.
- Susan F. Bailey
- , Aaron Hinz
- & Rees Kassen
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Article
| Open AccessRecurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour
Wilms tumour (WT) is the most common paediatric kidney cancer and few driver genes related to its development have been identified. Here, the authors identify DROSHAmutations that may contribute to WT tumorigenesis through their effect on primary microRNA processing.
- Giovana T. Torrezan
- , Elisa N. Ferreira
- & Dirce M. Carraro
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Epistasis and natural selection shape the mutational architecture of complex traits
Mutations are the source of genetic variation, yet the mechanisms determining the distribution of mutations are unclear. Here, Jones et al.show that gene interactions allow natural selection to shape the distribution of mutations, suggesting that mutations can be a biased source of genetic variation.
- Adam G. Jones
- , Reinhard Bürger
- & Stevan J. Arnold
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| Open AccessMutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy
Parkinson’s disease can be caused by a rare mutation in the protein VPS35, but the mechanism responsible for this is largely unknown. Here, Zavodszky et al.show that this mutation leads to defects in the recruitment of endosomal protein sorting machinery and consequent inhibition of autophagy in cells.
- Eszter Zavodszky
- , Matthew N.J. Seaman
- & David C. Rubinsztein
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Massive gene amplification drives paediatric hepatocellular carcinoma caused by bile salt export pump deficiency
Hepatocellular carcinoma (HCC) is associated with chronic inflammation, but the genetic basis of the disease remains unclear. Here, the authors report that defects in hepatocyte biliary transporters and subsequent liver inflammation induce genomic alterations that promote HCC in human and mouse.
- Fabio Iannelli
- , Agnese Collino
- & Francesca D. Ciccarelli
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Mutations in the PQBP1 gene prevent its interaction with the spliceosomal protein U5–15kD
Frameshift mutations in the protein polyglutamine tract-binding protein 1 (PQBP1) are believed to cause X-linked mental retardation. Here, Mizuguchi et al.present the crystal structure of a C-terminal fragment of PQBP1 in complex with the spliceosomal protein U5–15kD, and show details of this interaction that can lead to mechanistic insights into the disease.
- Mineyuki Mizuguchi
- , Takayuki Obita
- & Hitoshi Okazawa
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| Open AccessWhole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden
Bladder cancer is a complex genetic disease and a common cause of death due to malignancy. Here, the authors carry out whole-genome sequencing of 14 bladder cancers to characterize the genomic landscape of the disease and show that mutational burden is associated with tumour progression in these samples.
- J. -B. Cazier
- , S. R. Rao
- & F. C. Hamdy
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| Open AccessMutation rate plasticity in rifampicin resistance depends on Escherichia coli cell–cell interactions
The factors varying mutation rate at a particular site in a single genotype remain elusive. Here, Krašovec et al. show that mutation rates at sites conferring resistance to rifampicin in Escherichia coli decrease with population density, and that mutation-rate plasticity is controlled by the luxSgene.
- Rok Krašovec
- , Roman V. Belavkin
- & Christopher G. Knight
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| Open AccessThe rainbow trout genome provides novel insights into evolution after whole-genome duplication in vertebrates
Although whole-genome duplications (WGDs) are rare events, they have an important role in shaping vertebrate evolution. Here, the authors sequence the rainbow trout genome and show that rediploidization after WGD occurs in a slow and stepwise manner.
- Camille Berthelot
- , Frédéric Brunet
- & Yann Guiguen
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The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes
Proteins involved in epigenetic regulation are frequently mutated in several paediatric cancers. Here, Huether et al.characterize the somatic mutation frequency across 21 paediatric cancer subtypes by sequencing 633 epigenetic genes in over 1,000 tumours; generating a rich data set for investigating epigenetic dysregulation.
- Robert Huether
- , Li Dong
- & James R. Downing
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Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids
Pulmonary carcinoids account for about 2% of pulmonary neoplasms. Here, the authors carry out gene copy number analysis, genome/exome, and transcriptome sequencing of pulmonary carcinoids and identify frequent mutations in chromatin-remodelling genes that can drive tumorigenesis in these tumours.
- Lynnette Fernandez-Cuesta
- , Martin Peifer
- & Roman K. Thomas
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Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia
Epigenetic regulators have been proposed to be modulators of chemoresistance in acute lymphoblastic leukaemia. Here, the authors find enrichment of mutations in epigenetic regulators at relapse, including somatic mutations in SETD2.
- Brenton G. Mar
- , Lars B. Bullinger
- & Scott A. Armstrong
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Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma
Cutaneous melanoma is an aggressive form of skin cancer. Here, the authors show that mutations in the TERT promoter of 287 primary melanomas are associated with age, Breslow thickness and tumour ulceration and frequently occur at sun-exposed sites.
- Barbara Heidenreich
- , Eduardo Nagore
- & Rajiv Kumar
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| Open AccessThe origin of the bifurcated axial skeletal system in the twin-tail goldfish
The ornamental twin-tail goldfish has a bifurcated caudal skeleton that arose during domestication, but the developmental mechanisms that generate this tail are unknown. Here, Abe et al. show that a mutation in the chordingene affects embryonic dorsal–ventral patterning causing the bifurcated tail skeleton.
- Gembu Abe
- , Shu-Hua Lee
- & Kinya G. Ota
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Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy
N-methyl-D-aspartate receptors (NMDARs) are key regulators of neuronal excitability in the brain and NMDAR mutations are implicated in epilepsy. Here, the authors identify a NMDAR subunit mutation in a child with epileptic encephalopathy, and show that this mutation increases the activity of NMDAR channels.
- Hongjie Yuan
- , Kasper B. Hansen
- & Stephen F. Traynelis
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A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites
Genomes contain tracts of tandem guanines, which can adopt stable G-quadruplex structures that obstruct replication fork movement. Here, Koole et al. describe a non-canonical polymerase Theta-dependent repair pathway that prevents genomic instability caused by these replication barriers.
- Wouter Koole
- , Robin van Schendel
- & Marcel Tijsterman
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Global metabolic network reorganization by adaptive mutations allows fast growth of Escherichia coli on glycerol
Organisms can adapt to environmental change but how this affects metabolism is unclear. Here, the authors provide a detailed analysis of the effects of individual adaptive mutations on the metabolic network in E. coli, and find evidence of metabolic reprogramming during laboratory evolution on glycerol.
- Kian-Kai Cheng
- , Baek-Seok Lee
- & Martin Robert
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Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site
In Alzheimer’s disease, familial mutations of the amyloid precursor protein (APP) can increase the production of the toxic cleavage product Aß42. Here, Chen et al. show that mutations within the transmembrane domain of APP favour Aß42 production by increasing the accessibility of the ε-cleavage site.
- Wen Chen
- , Eric Gamache
- & Chunyu Wang
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Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1
Insulinomas develop from pancreatic β-cells and secrete insulin, but the underlying genetic defects are largely unknown. In this study, Cao et al. identify recurrent T372R mutations in the transcription factor YY1, and validate this hotspot mutation in 30% of insulinomas.
- Yanan Cao
- , Zhibo Gao
- & Guang Ning
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| Open AccessMutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups
Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the leading cancer among males in India. Here, the authors carry out exome sequencing and recurrence testing in patients with OSCC-GB and highlight genes and biological pathways associated with the disease.
- Arindam Maitra
- , Nidhan K. Biswas
- & D. Sutradhar
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Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition
Mutations in the GABA A receptor have been implicated in alcohol dependence in humans. In this study, the authors show that mice with mutations in the beta 1 subunit of the GABA A receptor exhibit spontaneous GABA A channel opening and preferentially consume alcohol, working harder to access it.
- Quentin M. Anstee
- , Susanne Knapp
- & Howard C. Thomas
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Rb1 family mutation is sufficient for sarcoma initiation
Loss of the tumour suppressor Rb1 alone is thought to be insufficient for tumorigenesis. In this study, Liu et al. demonstrate that cells in which all three Rb1 family members are inactivated can initiate tumour formation, but only if cell survival is ensured by the retention of cell–cell contacts.
- Yongqing Liu
- , Ester Sánchez-Tilló
- & Douglas C. Dean
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Cell–cell adhesion genes CTNNA2 and CTNNA3 are tumour suppressors frequently mutated in laryngeal carcinomas
Laryngeal carcinoma is a heterogeneous disease and multiple genes have been implicated in its pathogenesis. Here, Fanjul-Fernández et al. identify mutations in the cell–cell adhesion genes catenin α2 and catenin α3 in 15% of a cohort of homogeneous laryngeal carcinomas.
- Miriam Fanjul-Fernández
- , Víctor Quesada
- & Carlos López-Otín
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Functional evaluation of autism-associated mutations in NHE9
Mutations in the gene that encodes the endosomal cation/proton antiporter NHE9 are implicated in neuropsychiatric disorders. In this study, the authors screen autism-associated variants in the human population and identify specific variants of NHE9 that are characterized by a loss of function in astrocytes.
- Kalyan C. Kondapalli
- , Anniesha Hack
- & Rajini Rao
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Non-invasive in vivo assessment of IDH1 mutational status in glioma
The metabolic reaction catalysed by the isocitrate dehydrogenase 1 (IDH1) enzyme is commonly perturbed in some glioma subtypes due to gain-of-function mutations in the IDH1 gene. Here, Chaumeil et al.present a method that detects mutant IDH1 activity by measuring the levels of different hyperpolarized metabolites produced by wild-type and mutant IDH1.
- Myriam M. Chaumeil
- , Peder E. Z. Larson
- & Sabrina M. Ronen
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Genome architecture is a selectable trait that can be maintained by antagonistic pleiotropy
The contribution of chromosomal rearrangements to fitness remains to be directly quantified. By constructing rearrangements in fission yeast, the authors show that the resulting defects in meiosis may be compensated for by a strong growth advantage in mitosis.
- Ana Teresa Avelar
- , Lília Perfeito
- & Miguel Godinho Ferreira
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Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production
Clinical trials of γ-secretase inhibitors to treat Alzheimer’s disease show that side effects occur from their non-selective action. Dimitrov et al.show that improved second generation γ-secretase modulators spare cleavage sites of substrate proteins that are implicated in the side effects.
- Mitko Dimitrov
- , Jean-René Alattia
- & Patrick C. Fraering
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| Open AccessR-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli
DNA double-strand breaks commonly occur in all replicating cells. Wimberly and colleagues show that in non-replicating cells, aborted transcription/translation forms RNA/DNA hybrid R-loops that prime origin-independent replication, leading to DNA breakage, point mutations and chromosomal rearrangements.
- Hallie Wimberly
- , Chandan Shee
- & P. J. Hastings
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A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing
Cdt1 is part of a protein complex that regulates the initiation of DNA replication. Here Coulombe et al. identify a PEST-like regulatory domain in the N terminus of Cdt1 that prevents premature initiation of DNA synthesis during the cell cycle.
- Philippe Coulombe
- , Damien Grégoire
- & Marcel Méchali
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Article
| Open Accessβ-lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity
Sub-lethal concentrations of antibiotics are known to promote mutagenesis of bacterial DNA. Here the authors show that β-lactam antibiotics trigger mutagenesis by upregulating the stress-response protein RpoS, which downregulates mismatch-repair activity.
- A. Gutierrez
- , L. Laureti
- & I. Matic
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| Open AccessDisease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface
Ryanodine receptors are calcium-release channels located in the membrane of the sarcoplasmic and endoplasmic reticulum. Kimlicka et al.compare pseudo-atomic models of the N-terminal area in the open and closed states and characterize the mutations in the N-terminal that disrupt channel opening.
- Lynn Kimlicka
- , Kelvin Lau
- & Filip Van Petegem
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| Open AccessA point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration
Semaphorin 4A is implicated in photoreceptor survival. Nojima and colleagues generate transgenic mice with different mutations in the Sema4A gene and find that point mutation of F350 causes severe degeneration in photoreceptor cells, which can be rescued by virus-mediated gene therapy.
- Satoshi Nojima
- , Toshihiko Toyofuku
- & Atsushi Kumanogoh
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Analysis of protein-coding mutations in hiPSCs and their possible role during somatic cell reprogramming
Recent studies have shown that human induced pluripotent stem cells contain point mutations in coding regions, but the functional significance of these mutations is unclear. Here the authors provide evidence that these mutations are unlikely to confer a selective advantage for reprogramming.
- Sergio Ruiz
- , Athurva Gore
- & Juan Carlos Izpisua Belmonte
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Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells
Mutations in parkin, an ubiquitin ligase, cause an inherited form of Parkinson's disease. Here, Jianget al. generate induced pluripotent stem cells from two patients with parkin mutations and find that neurons derived from the stem cells have defects in dopamine release, dopamine uptake and oxidative metabolism.
- Houbo Jiang
- , Yong Ren
- & Jian Feng
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| Open AccessA segmental genomic duplication generates a functional intron
The appearance of a new intron that splits an exon without disrupting the corresponding peptide sequence is a rare event in vertebrate genomes. Hellstenet al.demonstrate that, under certain circumstances, a functional intron can be produced in a single step by segmental genomic duplication.
- Uffe Hellsten
- , Julie L. Aspden
- & Daniel S. Rokhsar
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Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome
Mutations in the DNA helicaseBLM cause Bloom syndrome, which is characterized by slow replication fork progression and genetic instability. Here, cells lacking BLMare shown to have a defect in cytidine deaminase, which alters the pyrimidine pool and results in replication fork progression with altered velocity.
- Pauline Chabosseau
- , Géraldine Buhagiar-Labarchède
- & Mounira Amor-Guéret
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| Open AccessIntestinal epithelial stem cells do not protect their genome by asymmetric chromosome segregation
It has been proposed that stem cells use nonrandom chromosome segregation to avoid the accumulation of replication-induced mutations. Here, the authors examine intestinal epithelial stem cell division and show, using label exclusion and retention assays, that the cells segregate their chromosomes randomly.
- Marion Escobar
- , Pierre Nicolas
- & Catherine Legraverend
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Human TSC2-null fibroblast-like cells induce hair follicle neogenesis and hamartoma morphogenesis
Mutations inTSC2 lead to the formation of benign tumours called hamartomas. In this study, using a mouse xenograft model, the authors demonstrate that fibroblasts from patients carrying TSC2mutations can induce keratinocytes to form both hair follicles and hamartoma-like growths with active mTOR signalling.
- Shaowei Li
- , Rajesh L. Thangapazham
- & Thomas N. Darling
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| Open AccessEffector diversification within compartments of the Leptosphaeria maculans genome affected by Repeat-Induced Point mutations
Leptosphaeria maculans is a plant pathogen that causes stem canker of oilseed rape. Rouxel et al. sequence and describe the key features of the L. maculansgenome, including partitioning into AT-rich blocks that are enriched in effector genes and transposable elements affected by repeat-induced point mutation.
- Thierry Rouxel
- , Jonathan Grandaubert
- & Barbara J. Howlett