Featured
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Article
| Open Access
Systematic analysis of somatic mutations impacting gene expression in 12 tumour types
Assessing functional impact of mutations in cancer on gene expression can improve our understanding of cancer biology and may identify potential therapeutic targets. Here, Ding et al. describe a novel statistical model named xseq for a systematic survey of how mutations impact transcriptome landscapes across 12 different tumour types.
- Jiarui Ding
- , Melissa K. McConechy
- & Sohrab P. Shah
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| Open Access
A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li–Fraumeni-like families
Genetic factors that cause cardiac angiosarcoma are unknown. Calveteet al. show that a missense mutation in protection of telomeres1 (POT1) gene causes cardiac angiosarcoma by affecting the POT1 function and, consequently, telomere length and stability.
- Oriol Calvete
- , Paula Martinez
- & Javier Benítez
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| Open Access
Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures
The potassium-chloride co-transporter, KCC2 is an essential component in maintaining a gradient for chloride ions in neurons. Here Stodberg and colleagues identify loss-of-function mutations in the encoding geneSLC12A5, which impair normal synaptic function associated with early-onset epilepsy.
- Tommy Stödberg
- , Amy McTague
- & Manju A. Kurian
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| Open Access
Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis
Primary lymphoedema can lead to the swelling of the extremities and facial dysmorphism. Here the authors present evidence that compound heterozygous and homozygous mutations inPIEZO1result in an autosomal recessive form of generalised lymphatic dysplasia.
- Elisavet Fotiou
- , Silvia Martin-Almedina
- & Pia Ostergaard
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| Open Access
Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans
Genomic imprinting disturbance can give rise to complex congenital disorders affecting growth, metabolism and behaviour. Here the authors report mutations inNLRP5, which suggests a connection between imprinting, maternal reproductive fitness and zygotic development.
- Louise E. Docherty
- , Faisal I. Rezwan
- & Deborah J. G. Mackay
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| Open Access
Mutations in CDCA7 and HELLS cause immunodeficiency–centromeric instability–facial anomalies syndrome
Immunodeficiency-centromeric instability-facial anomalies syndrome is a life threatening autosomal recessive disorder caused by mutations in DNMT3B and ZBTB24. Here Thijssen et al. identify mutations in CDCA7 and HELLSin previously unexplained cases.
- Peter E. Thijssen
- , Yuya Ito
- & Hiroyuki Sasaki
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| Open Access
D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2
IDH1- and IDH2-mutant cancer cells aberrantly accumulate D2-hydroxyglutarate (D2-HG). Here, Lin et al. find loss-of-function mutations in D2-hydroxyglutarate dehydrogenase (D2HGDH), which converts D2-HG to alpha-ketoglutarate (α-KG), in diffuse large B-cell lymphomas and show that D2HGDH via α-KG regulates the expression and activity of IDH2.
- An-Ping Lin
- , Saman Abbas
- & Ricardo C. T. Aguiar
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| Open Access
SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation
Synapsins anchor synaptic vesicles (SVs) to the actin cytoskeleton to establish the reserve vesicle pool. Here Tanget al. show that SUMOylation of synapsin 1a enhances its interaction with SVs to promote efficient reclustering following stimulation, and a mutation linked to autism and epilepsy leads to defective SUMOylation.
- Leo T. -H. Tang
- , Tim J. Craig
- & Jeremy M. Henley
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| Open Access
Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III
Some RNA polymerase (POLR) 3-related leukodystrophy cases do not have the causal mutations in POLR3A and POLR3B. Here, by exome sequencing, the authors identify recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, impairing assembly and nuclear import of POLR3, but not POLR1.
- Isabelle Thiffault
- , Nicole I. Wolf
- & Geneviève Bernard
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Article
| Open Access
Identification of mammalian-adapting mutations in the polymerase complex of an avian H5N1 influenza virus
Understanding the factors that enable some bird flu viruses to infect humans is important for the identification of circulating viruses with higher potential to infect us. Here, Taft et al.identify novel mutations in the polymerase of an avian H5N1 virus that help the virus to replicate in human cells and in mice
- Andrew S. Taft
- , Makoto Ozawa
- & Yoshihiro Kawaoka
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| Open Access
De novo mutations in PLXND1 and REV3L cause Möbius syndrome
lt has been debated for decades if there is a genetic aetiology underlying Möbius syndrome, a neurological disorder characterized by facial paralysis. Here Tomas-Roca et al. use exome sequencing and identify de novo mutations in PLXND1 and REV3L, representing converging pathways in hindbrain development.
- Laura Tomas-Roca
- , Anastasia Tsaalbi-Shtylik
- & Hans van Bokhoven
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| Open Access
TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport
Severe congenital development defects such as Jeune syndrome can result from the malfunction of primary cilia and dynein. Here Schmidts et al. report unique biallelic null mutations in a gene encoding a dynein light chain, helping to explain the nature of ciliopathies in human patients.
- Miriam Schmidts
- , Yuqing Hou
- & Hou-Feng Zheng
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Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms
Structural variation is a major source of complexity in the human genome. Here Abyzov et al.present the identification, classification and analysis of a large database of variants giving an insight into mechanisms generating them.
- Alexej Abyzov
- , Shantao Li
- & Mark B. Gerstein
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Oncogenes create a unique landscape of fragile sites
Aberrant oncogene expression can cause replication stress leading to chromosomal breaks. Here the authors map the chromosomal break loci induced by two different oncogenes and by a replication inhibitor, and show that each treatment induces a unique pattern of breaks in the same cell type.
- Karin Miron
- , Tamar Golan-Lev
- & Batsheva Kerem
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| Open Access
Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy
Phospholamban (PLN) is a regulator of heart contractility. Here the authors show that cardiomyocytes derived from induced pluripotent stem cells of a cardiomyopathy patient with mutant PLN exhibit functional defects consistent with the disease, and that this mutation can be functionally corrected by genome editing and gene therapy.
- Ioannis Karakikes
- , Francesca Stillitano
- & Roger J. Hajjar
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Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate
RAS, identified over 30 years ago as a potent oncogene, is one of the most commonly mutated genes in cancer. Here the authors show that KR12, an alkylating reagent that specifically cleaves the DNA coding for the G12D and G12V activated variants of KRAS, limits the growth of KRAS mutant cells in vitro and in vivo.
- Kiriko Hiraoka
- , Takahiro Inoue
- & Hiroki Nagase
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Article
| Open Access
C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle
SHGC syndrome affects cattle and has clinical features similar to human Seckel syndrome. Here Floriot et al. identify the causative mutation in the centrosomal protein C-Nap1 that affects centriole cohesion and cell migration, extending the range of loci involved in human Seckel-like syndromes.
- Sandrine Floriot
- , Christine Vesque
- & Laurent Schibler
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RECQ5-dependent SUMOylation of DNA topoisomerase I prevents transcription-associated genome instability
DNA topoisomerase I (TOP1) maintains DNA topology by relaxing supercoiled DNA during transcription. Here, the authors show that SUMOylation of TOP1 is necessary for its association with transcriptionally active RNA polymerase II and can reduce R-loops, preventing TOP1-induced DNA damage.
- Min Li
- , Subhash Pokharel
- & Yilun Liu
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Article
| Open Access
Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control
Defects in the DNA replication checkpoint can lead to genomic instability and cancer. Here the authors show that Cmr1/WDR76 participates in the DNA replication stress response and—along with several other components—defines a new cellular compartment that forms during cellular stress.
- Irene Gallina
- , Camilla Colding
- & Michael Lisby
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| Open Access
The genome-wide effects of ionizing radiation on mutation induction in the mammalian germline
Ionizing radiation (IR) is an extensively studied mutagenic agent that can lead to the accumulation of extra mutations in the offspring of irradiated parents. Here the authors provide a comprehensive genome-wide survey of the consequences of IR on the mammalian germline.
- Adeolu B. Adewoye
- , Sarah J. Lindsay
- & Matthew E. Hurles
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| Open Access
Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution
Papillary renal cell carcinoma (pRCC) is a subtype of kidney cancer characterized by highly variable clinical behaviour. Here the authors sequence either the genomes or exomes of 31 pRCCs and identify several genes in sub-clones and large copy number variants in major clones that may be important drivers of pRCC.
- Michal Kovac
- , Carolina Navas
- & Ian Tomlinson
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| Open Access
The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment
Autism genes converge in midfetal cortical co-expression networks, and chromatin regulators such as CHD8 are increasingly associated with autism spectrum disorder (ASD). Here the authors map CHD8 targets in developing brain, and find that CHD8 directly regulates other ASD risk genes during human neurodevelopment.
- Justin Cotney
- , Rebecca A. Muhle
- & James P. Noonan
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CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling
Mutations in the CCM3 gene in humans lead to severe forms of cerebral cavernous malformation. Here, Lant et al. shed light on the mechanism of CCM-3 function in C. elegans, and show that CCM-3 ablation leads to defects in excretory canal extension and the formation of cysts reminiscent of human malformations.
- Benjamin Lant
- , Bin Yu
- & W Brent Derry
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Remodelling of a homeobox gene cluster by multiple independent gene reunions in Drosophila
Gene clusters of paralogous genes are thought to result from tandem gene duplications. Here, the authors show two independent reunions of homeobox genes in Drosophila, which suggests that large-scale chromosomal rearrangements play a role in reshaping paralogous gene clustering.
- Carolus Chan
- , Suvini Jayasekera
- & José M. Ranz
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| Open Access
3D hotspots of recurrent retroviral insertions reveal long-range interactions with cancer genes
Retroviral insertional mutagenesis is used for identifying genes involved in the development of cancer. Here, the authors overlay cancer-causing insertions with genome-wide Hi-C data and find that retroviral elements tend to cluster in 3D hotspots.
- Sepideh Babaei
- , Waseem Akhtar
- & Jeroen de Ridder
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| Open Access
Arabidopsis MSH1 mutation alters the epigenome and produces heritable changes in plant growth
Suppression of MutS HOMOLOGUE 1 (MSH1), a plant protein targeted to mitochondria and plastids, causes a variety of phenotypes. Here Virdi et al. show that MSH1 depletion in Arabidopsisresults in heritable changes in nuclear DNA methylation, which can lead to enhanced growth vigour.
- Kamaldeep S. Virdi
- , John D. Laurie
- & Sally A. Mackenzie
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TMC-1 attenuates C. elegans development and sexual behaviour in a chemically defined food environment
The tmc-1 gene encodes for a sodium channel that has been linked to chemosensation in C. elegans. Here the authors show that in a non-optimal nutrient environment, tmc-1mediates physiological worm responses such as developmental retardation and inhibited sexual behaviour.
- Liusuo Zhang
- , Daisy G. Gualberto
- & L. Rene Garcia
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Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy
Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. Here, Ousterout et al. use multiplexed CRISPR/Cas9 genome editing to excise a large portion of the gene that carries over 60% of known dystrophin mutations. They show that this excision restores dystrophin expression in patient-derived cells.
- David G. Ousterout
- , Ami M. Kabadi
- & Charles A. Gersbach
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Unique features of mutations revealed by sequentially reprogrammed induced pluripotent stem cells
Mice can be generated from induced pluripotent stem cells (iPSCs) but the impact of accumulated mutations on the developmental potential of the cells remains to be determined. Here the authors show that mice generated from iPSCs tolerate the accumulation of somatic mutations for up to six generations, but their viability decreased with increasing generations.
- Shuai Gao
- , Caihong Zheng
- & Shaorong Gao
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Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension
Transcription factor Nr2f2 is linked to high blood pressure in humans and animals. Using hypertensive rats that have been genetically modified to express a mutant Nr2f2 that binds stronger to transcription factor Fog2, the authors show that the interaction between these two proteins is critical for blood pressure regulation.
- Sivarajan Kumarasamy
- , Harshal Waghulde
- & Bina Joe
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Article
| Open Access
Macrotene chromosomes provide insights to a new mechanism of high-order gene amplification in eukaryotes
Copy number variation is an important source of genetic variation in natural populations and may have a role in human disease. Here, the authors identify high-order amplification structures that form large extended chromosomes and suggest that these may occur due to accidental template switching in stress conditions.
- Agnès Thierry
- , Varun Khanna
- & Bernard Dujon
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Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity
Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma displaying biliary phenotypes are aggressive cancers. Fujimoto et al. characterize the mutational profile of chronic hepatitis and identify mutations in KRAS and IDHassociated with poor survival.
- Akihiro Fujimoto
- , Mayuko Furuta
- & Hidewaki Nakagawa
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| Open Access
Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179
The rd1 mouse is the most widely used model to study retinal degeneration. Here, the authors identify a wide-spread mutation in these mice that may explain the failure of previous gene therapeutic approaches and show that long-lasting restoration of vision is possible in rd1 mice without this mutation.
- Koji M. Nishiguchi
- , Livia S. Carvalho
- & Robin R. Ali
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Article
| Open Access
Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here, the authors sequence the whole exomes of 42 TGCTs, and characterize the mutational profile of this tumour type.
- Kevin Litchfield
- , Brenda Summersgill
- & Clare Turnbull
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Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma
Intrahepatic cholangiocarcinoma is an aggressive cancer of the bile duct with few treatment options and a below 10% five-year survival rate. Here Sia et al. show a novel FGFR2–PPHLN1 fusion and ARAFmutations that may represent future potential therapeutic targets.
- Daniela Sia
- , Bojan Losic
- & Josep M. Llovet
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Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas
Pheochromocytomas and paragangliomas (PCC/PGL) are tumours of the autonomic nervous system. Here, the authors identify ATRX mutations in PCC/PGL and suggest that ATRXloss is important for tumorigenesis in a subset of PCC/PGL.
- Lauren Fishbein
- , Sanika Khare
- & Katherine L. Nathanson
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ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning
Protein kinase NEK8 is important for cilliary function, but the mechanism by which it acts is unknown. Czarnecki et al. identify the cilliary protein ANKS6 as a target and crucial activator of NEK8 and describe the importance of this protein interaction in embryonic development and organogenesis.
- Peter G. Czarnecki
- , George C. Gabriel
- & Jagesh V. Shah
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Article
| Open Access
Origins of multicellular evolvability in snowflake yeast
The first steps in the transition to multicellularity remain poorly understood. Here, the authors demonstrate that disrupting a single gene in yeast results in multicellular clusters that develop clonally and possess a high degree of multicellular heritability, predisposing them to multicellular adaptation.
- William C. Ratcliff
- , Johnathon D. Fankhauser
- & Michael Travisano
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| Open Access
Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios
The generation of a national pan-genome, a population-specific catalogue of genetic variation, may advance the impact of clinical genetics studies. Here the Besenbacher et al. carry out deep sequencing and de novo assembly of 10 parent–child trios to generate a Danish pan-genome that provides insight into structural variation, de novomutation rates and variant calling.
- Søren Besenbacher
- , Siyang Liu
- & Simon Rasmussen
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Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome
Somatic mutations in components of the core RNA splicing machinery, including ZRSR2, have been implicated in myelodysplastic syndrome (MDS). Here, Madan et al.show that ZRSR2 plays a pivotal role in splicing of the U12-type introns, while the U2-dependent splicing is largely unaffected in ZRSR2 mutant MDS bone marrow.
- Vikas Madan
- , Deepika Kanojia
- & H. Phillip Koeffler
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Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells
NK-cell and γδ-T cell lymphoma share clinic-pathological features; however the driving mutations are largely unknown. Here the authors, using a combination of RNA-Seq analysis, targeted re-sequencing and functional analysis, identify frequent activating mutations in STAT3 and STAT5Bthat may be driver mutations in these diseases.
- Can Küçük
- , Bei Jiang
- & Wing C. Chan
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Article
| Open Access
Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes
The myelodysplastic syndromes (MDS) are a heterogeneous group of chronic blood cancers. Here, the authors analyse genomic and gene expression data from MDS patients to investigate how driver mutations alter gene expression, diagnostic clinical variables and survival.
- Moritz Gerstung
- , Andrea Pellagatti
- & Jacqueline Boultwood
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Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness
Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. Here the authors link mutations in the gene PNPLA6 with childhood blindness in seven families with retinal degeneration and show that the gene plays a role in photoreceptor survival in Drosophila.
- S. Kmoch
- , J. Majewski
- & R. K. Koenekoop
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| Open Access
Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle
The hormone prolactin is a known modulator of mammalian lactation and hair growth. Here, the authors describe two dominant mutations in bovine prolactin and its receptor, demonstrating antagonistic effects on these traits and highlighting a role for this pathway in sweat gland function and thermoregulation.
- Mathew D. Littlejohn
- , Kristen M. Henty
- & Stephen R. Davis
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Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival
Chemical inhibitors of the tumour-progression promoting arachidonic acid metabolism pathway prolong post-treatment survival of cancer patients. Here the authors analyse sequence variation in oral cancer patients and show that loss-of-function mutations in this pathway prolong survival.
- Nidhan K. Biswas
- , Subrata Das
- & Partha P. Majumder
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Mutational landscape of intrahepatic cholangiocarcinoma
Intrahepatic cholangiocarcinoma (ICC) is a fatal primary liver cancer with a known genetic component. Here the authors sequence the exomes of matched tumour and normal tissue from 103 ICC patients in China, and identify an ICC mutational profile associated with liver inflammation, fibrosis and cirrhosis.
- Shanshan Zou
- , Jiarui Li
- & Heping Hu
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PKA catalytic subunit mutations in adrenocortical Cushing’s adenoma impair association with the regulatory subunit
Cushing’s adenoma is associated with somatic mutations in the gene encoding the Cα subunit of protein kinase A. Calebiro et al.reveal that these mutations increase protein kinase A activity by preventing proper assembly of the protein kinase A holoenzyme.
- Davide Calebiro
- , Annette Hannawacker
- & Martin J. Lohse
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Extrachromosomal driver mutations in glioblastoma and low-grade glioma
Human cancers are characterised by increased levels of genomic instability. Here, the authors show that a new class of mutation that occurs in glioblastoma, double minutes, may facilitate tumour drug resistance by acquiring gain-of-function extrachromosomal mutations, mediated by focal amplifications.
- Sergey Nikolaev
- , Federico Santoni
- & Stylianos E. Antonarakis
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Recurrent de novo mutations implicate novel genes underlying simplex autism risk
Autism spectrum disorder (ASD) is a common disorder with a strong and complex genetic component. Here, the authors resequence 64 candidate neurodevelopmental disorder risk genes in almost 6,000 samples and identify novel genes associated with ASD.
- B. J. O'Roak
- , H. A. Stessman
- & E. E. Eichler
Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization