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Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.
- Markus Bender
- , Simon Stritt
- & Bernhard Nieswandt
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| Open Accessptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease
Scoliosis is a complex genetic disorder characterized by spinal curvature. Here, the authors present experimental zebrafish models of idiopathic and congenital scoliosis and suggest a role for dysregulated Wnt activity in scoliosis aetiology.
- Madeline Hayes
- , Xiaochong Gao
- & Brian Ciruna
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Cardiac arrhythmia induced by genetic silencing of ‘funny’ (f) channels is rescued by GIRK4 inactivation
The ‘funny’ current (If) is important for the generation and regulation of the heart’s automaticity. Here the authors show that If silencing through genetic modification of the f-channel component HCN4 causes heart arrhythmia by altering Ca2+handling in pacemaker myocytes.
- Pietro Mesirca
- , Jacqueline Alig
- & Matteo E. Mangoni
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Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women
Ovarian cancer is common among women and is the leading cause of death from gynaecological malignancies. Here the authors identify two previously unknown genetic variants that increase the risk of epithelial ovarian cancer in Han Chinese women.
- Kexin Chen
- , Hongxia Ma
- & Qingyi Wei
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Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations
For children with acute lymphoblastic leukaemia (ALL), those with Down syndrome (DS) have decreased survival compared with children without DS. Here, the authors use exome sequencing to characterise the mutational landscape of patients with both ALL and DS and highlight genes related to survival and relapse.
- Sergey I. Nikolaev
- , Marco Garieri
- & Stylianos E. Antonarakis
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| Open AccessSelective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model
Tuberous sclerosis complex (TSC) is a rare genetic condition characterized by epileptic seizures that start in infancy. Here, the authors show that these seizures are modulated by GluN2C-containing NMDA receptors in the cortex of a mouse model of TSC, and that suppressing their activity attenuates seizures.
- N. Lozovaya
- , S. Gataullina
- & N. Burnashev
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MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia
Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder, characterized by chronic airway disease. Here, the authors identify mutations in the Multicilin gene, MCIDAS, and suggest that these mutations cause RGMC through disruption of multiciliated cell differentiation.
- Mieke Boon
- , Julia Wallmeier
- & Heymut Omran
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Elfn1 recruits presynaptic mGluR7 in trans and its loss results in seizures
The transmembrane protein Elfn1 is implicated in synaptic plasticity. Tomioka et al. identify Elfn1 mutations in epilepsy and attention deficit hyperactivity disorder (ADHD) patients, and show that loss of Elfn1in mice results in seizures, ADHD-like behaviour and impaired development of excitatory synapses.
- Naoko H. Tomioka
- , Hiroki Yasuda
- & Jun Aruga
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| Open AccessDisrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome
Cerebro–costo–mandibular syndrome, CCMS, is a severe human multiple malformation disorder. Here, the authors report that mutations in SNRPBdisrupt the normal regulation of alternative splicing at this gene, and in so doing, may be responsible for the development of CCMS.
- Danielle C. Lynch
- , Timothée Revil
- & Francois P. Bernier
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| Open AccessA gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase
How the substrate specificity of fatty aldehyde dehydrogenase (FALDH) towards long-chain aldehydes is achieved is an unresolved question. Here the authors present a crystal structure of human membrane-bound FALDH and find that it contains a ‘gatekeeper’ helix that directs substrate specificity towards long-chain fatty aldehydes.
- Markus A. Keller
- , Ulrich Zander
- & Jose A. Marquez
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Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction
It is becoming increasingly clear that the three-dimensional organization of chromatin within the nucleus plays a role in regulating gene expression. Here, Ito et al.demonstrate that the disruption of chromocenter clustering in mature neuronal cells results in specific transcriptional and behavioural defects in mice.
- Satomi Ito
- , Adriana Magalska
- & Angel Barco
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Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men
Differential selection on sex-specific genes facilitates propagation of deleterious mutations. Here, the authors show that genes exclusively expressed in human testes harbour a greater number of deleterious mutations than genes expressed in both sexes, due to reduced selection in females.
- Moran Gershoni
- & Shmuel Pietrokovski
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Merotelic attachments allow alignment and stabilization of chromatids in meiosis II oocytes
Chromosome mis-segregation is a frequent occurrence in meiosis. Here the authors show that single unpaired chromatids avoid the spindle assembly checkpoint in the second meiotic division as they form bi-directional microtubule–kinetochore attachments, which leads to the completion of meiosis and the establishment of aneuploidy.
- Anna Kouznetsova
- , Abrahan Hernández-Hernández
- & Christer Höög
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Sequencing-based approach identified three new susceptibility loci for psoriasis
Although psoriasis is a chronic disorder affecting approximately 2% of the population, little is known about the underlying genetic architecture. Here, the authors carry out exome sequencing in a large Han Chinese cohort of psoriasis patients and healthy controls, and identify three new genes that may increase risk of developing the disease.
- Yujun Sheng
- , Xin Jin
- & Xuejun Zhang
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| Open AccessEXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia
The exosome is responsible for mRNA degradation, which is an important step in the regulation of gene expression. Here the authors report that homozygous missense mutations in the exosome subunit, EXOSC8, may cause neurodegenerative disease in infants through the dysregulation of myelin expression.
- Veronika Boczonadi
- , Juliane S. Müller
- & Rita Horvath
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| Open AccessTM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is characterized by increased hepatic triglyceride content (HTGC) in the absence of high alcohol consumption. Here the authors show that a genetic variant in TM6SF2, which is known to be associated with HTGC, is a clinically relevant modifier of hepatic fibrogenesis and increases the risk of progressive NAFLD.
- Yang-Lin Liu
- , Helen L. Reeves
- & Quentin M. Anstee
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Low-grade chromosomal mosaicism in human somatic and embryonic stem cell populations
De novocopy number variations are known to occur in somatic cell populations and pluripotent stem cells. Here the authors use single-cell array comparative genomic hybridization to identify copy number variations in individual human somatic and embryonic stem cells.
- Kurt Jacobs
- , Afroditi Mertzanidou
- & Claudia Spits
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| Open AccessThe impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
The autism spectrum disorders are complex genetic traits characterized by various neurodevelopmental deficits. Here, the authors analyse defective gene family interaction networks in autism cases and healthy controls and identify potential gene family interactions that may contribute to autism aetiology.
- Dexter Hadley
- , Zhi-liang Wu
- & Hakon Hakonarson
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Genome-wide association study identifies three novel susceptibility loci for severe Acne vulgaris
Acne vulgarisis a common, inflammatory skin disorder. Here the authors carry out a genome-wide association study and identify three genetic variants that associate with an increased risk of developing acne, which together suggest a mechanistic role for the TGFβ cell signalling pathway in acne development and progression.
- Alexander A. Navarini
- , Michael A. Simpson
- & Jonathan N. Barker
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iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis
Mutations in the gene, GBA1, cause Gaucher’s disease, and are a strong risk factor for the development of Parkinson’s disease. Here the authors use cells derived from Parkinson’s patients with GBA1mutations to model the disease, and reveal changes in cellular recycling systems that may promote neurodegeneration.
- David C. Schöndorf
- , Massimo Aureli
- & Michela Deleidi
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Engineering human tumour-associated chromosomal translocations with the RNA-guided CRISPR–Cas9 system
CRISPR and Cas9 are endonucleases that are found in bacteria and have recently been exploited for genome engineering. Here, the authors use this system in cultured mammalian cells to engineer chromosomal translocations that are found in acute myeloid leukaemia and Ewing’s sarcoma.
- R. Torres
- , M. C. Martin
- & S. Rodriguez-Perales
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De novo SOX11 mutations cause Coffin–Siris syndrome
Coffin–Siris syndrome (CSS) is a genetic disorder characterized by growth deficiency, microcephaly, intellectual disability and nail hypoplasia of the fifth digits. Here, the authors identify de novo mutations in the SOX11 gene of CSS patients and show that knockdown of sox11a/bcauses brain abnormalities in zebrafish.
- Yoshinori Tsurusaki
- , Eriko Koshimizu
- & Naomichi Matsumoto
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Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size
Mutations in WD-repeat-containing protein 62 (Wdr62) are associated with microcephaly, a congenital disorder characterized by reduced brain size. The authors show that Wdr62 deficiency in mouse embryos leads to mitotic arrest of neural progenitors and that Wdr62 genetically interacts with Aurora kinase Ato control mitotic progression of neural progenitors.
- Jian-Fu Chen
- , Ying Zhang
- & Lee Niswander
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Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men
Non-obstructive azoospermia (NOA) is a major cause of male infertility. Here, the authors provide insight into the genetic basis of NOA by identifying three new genetic risk loci in a genome-wide association study and reporting a fourth potential NOA susceptibility locus based on a Drosophilaknockdown experiment.
- Zhibin Hu
- , Zheng Li
- & Jiahao Sha
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| Open AccessProtein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism
Autism spectrum disorder (ASD) is a complex genetic trait that encompasses a range of neurodevelopmental disorders. Here, the authors clone brain-expressed alternatively-spliced isoforms of ASD risk factors and construct a network of protein interactions that provides further insight into the disease aetiology.
- Roser Corominas
- , Xinping Yang
- & Lilia M. Iakoucheva
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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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| Open AccessSLC7A14 linked to autosomal recessive retinitis pigmentosa
Retinitis pigmentosa is the leading cause of inherited blindness worldwide. Here, the authors use exome sequencing to identify mutations in SLC7A14that may be linked to the disease, and provide functional support for the role of this gene in retinal development and visual function in mice and zebrafish.
- Zi-Bing Jin
- , Xiu-Feng Huang
- & Jia Qu
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Non-canonical function of spindle assembly checkpoint proteins after APC activation reduces aneuploidy in mouse oocytes
The spindle assembly checkpoint (SAC) has been viewed as a switch that prevents chromosome segregation until all chromosomes are correctly attached to spindle microtubules. Lane and Jones show that in meiosis I, SAC proteins remain partially active after prometaphase, and prevent aneuploidy by prolonging meiosis.
- Simon I.R. Lane
- & Keith T. Jones
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Genome-wide association study reveals two new risk loci for bipolar disorder
Bipolar disorder (BD) is a severe mood disorder, which has been shown to have a large genetic component. Here the authors identify two previously unreported BD risk loci and provide further insights into the biological mechanisms underlying BD development.
- Thomas W. Mühleisen
- , Markus Leber
- & Sven Cichon
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Mutations in Alström protein impair terminal differentiation of cardiomyocytes
Cardiomyocyte cell cycle arrest is important for mammalian heart maturation, but the process is poorly understood. Here, the authors use exome sequencing to identify compound heterozygous ALMS1mutations associated with cardiomyocyte replication and provide evidence that Alström protein deficiency impairs postnatal cardiomyocyte cell cycle arrest.
- Lincoln T. Shenje
- , Peter Andersen
- & Daniel P. Judge
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Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue
The effects of genetic variation on DNA methylation patterns are poorly understood. Here, Shi et al.systematically map methylation-quantitative trait loci in lung, breast and kidney tissue to reveal the impact of inherited variation on the human methylome, which also affects cancer risk.
- Jianxin Shi
- , Crystal N. Marconett
- & Maria Teresa Landi
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A non-canonical function of telomerase RNA in the regulation of developmental myelopoiesis in zebrafish
The telomerase reverse transcriptase promotes the development of haematopoietic cells in zebrafish independent of its telomere-lengthening activity. Here Alcaraz-Pérez et al.show that the telomerase RNA component regulates cell fate during zebrafish myelopoiesis also in a non-canonical manner.
- Francisca Alcaraz-Pérez
- , Jesús García-Castillo
- & María L. Cayuela
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Two new susceptibility loci 1q24.2 and 11p11.2 confer risk to severe acne
Severe acne is a common skin disease characterized by chronic inflammation and potential scarring. Here, the authors have identified genetic variants at two loci associated with severe acne and provide insight into the genetic architecture and biological pathways underlying the disease.
- Li He
- , Wen-Juan Wu
- & Ya-Ping Zhang
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| Open AccessRibosome profiling reveals features of normal and disease-associated mitochondrial translation
Mitochondrial ribosomes are uniquely affected by mutations in the mitochondrial genome. By mapping the position of ribosomes on transcripts, the authors here reveal functional differences between mitochondrial and cytosolic ribosomes, and show that mutations in mitochondrial tRNAs induce ribosome stalling.
- Koos Rooijers
- , Fabricio Loayza-Puch
- & Reuven Agami
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| Open AccessGenome-wide association study implicates NDST3 in schizophrenia and bipolar disorder
Schizophrenia and bipolar disorder are important psychiatric disorders with overlapping genetic components. Here, the authors identify and replicate a genome-wide significant risk locus for the two disorders, and suggest a role for NDST3in severe psychiatric disease.
- Todd Lencz
- , Saurav Guha
- & Ariel Darvasi
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| Open AccessPlatelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A
Haemophilia is a genetic bleeding disorder associated with a deficiency in the coagulation factor VIII. Here, the authors use gene therapy to achieve stable overexpression of factor VIII in platelets of dogs with haemophilia A, preventing the occurrence of severe bleeding episodes for over 2.5 years.
- Lily M. Du
- , Paquita Nurden
- & David A. Wilcox
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| Open AccessA molecular explanation for the recessive nature of parkin-linked Parkinson’s disease
Mutations in the E3 ubiquitin ligase parkin are associated with juvenile Parkinson’s disease. Here the authors report the solution structure of the Parkin RING2 domain, revealing how disease-associated mutations affect its function and providing a molecular explanation for the recessive nature of the disease.
- Donald E. Spratt
- , R Julio Martinez-Torres
- & Gary S. Shaw
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Stac3 is a component of the excitation–contraction coupling machinery and mutated in Native American myopathy
Skeletal muscle contractions are regulated by a process known as excitation–contraction coupling (ECC), defects in which can cause myopathies. Here Horstick et al.show that the protein STAC3 is a component of the ECC machinery and identify mutations in STAC3 as the cause of Native American Myopathy.
- Eric J. Horstick
- , Jeremy W. Linsley
- & John Y. Kuwada
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Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels
Dehydrated hereditary stomatocytosis is a genetic condition in which the permeability of red blood cells to cations in increased. Albuisson and colleagues find that mutations in the mechanically-activated PIEZO1 ion channel are the major cause of the disease and result in more slowly inactivating currents.
- Juliette Albuisson
- , Swetha E Murthy
- & Ardem Patapoutian
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R-Spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea
Citrobacter rodentiumis an intestinal pathogen of mice widely used to model enteropathogenicE. coli infection in humans. Using a forward genetic approach, Papapietro and colleagues identify R-Spondin 2 expression and resulting Wnt signalling activation as a major regulator of C. rodentium-induced colitis.
- Olivier Papapietro
- , Sarah Teatero
- & Samantha Gruenheid
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Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations
Palindromic DNA sequences in the genome can cause gross chromosomal rearrangements. Inagaki et al.demonstrate how the pathways of Holliday-junction resolution and antigen-receptor gene rearrangement interact to process cruciform conformation of palindrome DNA into chromosomal translocations in human embryonic kidney cells.
- Hidehito Inagaki
- , Tamae Ohye
- & Hiroki Kurahashi
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An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells
Patient-specific induced pluripotent stem (iPS) cells hold great potential for regenerative cell therapies. Here Filareto et al. genetically correct iPS cells from mice with muscular dystrophy and use these cells to treat the same animals, providing a proof-of-principle for autologous iPS cell therapy.
- Antonio Filareto
- , Sarah Parker
- & Rita C. R. Perlingeiro
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A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology
The mislocalization and downregulation of the proteins TDP-43 and ADAR2, respectively, are implicated in amyotrophic lateral sclerosis pathology. Yamashita et al. find that downregulation of ADAR2 results in calcium-permeable AMPA receptor-mediated calpain activation and subsequent aberrant cleavage of TDP-43.
- Takenari Yamashita
- , Takuto Hideyama
- & Shin Kwak
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| Open AccessDynamic blastomere behaviour reflects human embryo ploidy by the four-cell stage
Abnormal human embryo development is implicated in the embryo arrest observed during in vitrofertilization. Chavez and colleagues perform time-lapse imaging on human embryos and find that chromosomally abnormal embryos exhibit diverse cell cycle parameters that may contribute to arrest.
- Shawn L. Chavez
- , Kevin E. Loewke
- & Renee A. Reijo Pera
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| Open AccessUncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome
Fragile X syndrome is a major genetic cause of autism and is caused by loss of the fragile X mental retardation protein. In a mouse model of fragile X syndrome, Junget al. show that an absence of neuronal endocannabinoid signalling is responsible for the neurophysiological and behavioural defects.
- Kwang-Mook Jung
- , Marja Sepers
- & Olivier J. Manzoni
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Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology
The protein α-synuclein is implicated in Parkinson's disease. Rhinn and colleagues perform gene expression analysis and find that specific α-synuclein transcripts are preferentially associated with Parkinson's disease, and that they potentiate the accumulation of α-synuclein protein.
- Herve Rhinn
- , Liang Qiang
- & Asa Abeliovich
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Production of α-L-iduronidase in maize for the potential treatment of a human lysosomal storage disease
The lysosomal storage disease mucopolysaccharidosis I is treated with recombinant α-L-iduronidase but production of the enzyme is expensive. In this study, α-L-iduronidase is compartmentalized within the endosperm of maize via a unique mRNA strategy yielding the active, correctly glycosylated protein.
- Xu He
- , Thomas Haselhorst
- & Allison R. Kermode
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| Open AccessABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer
In mammalian cells, ABC transporter proteins were thought to exclusively export a range of substrates out of cells. Quazi and colleagues show that, in retinal photoreceptor cells, ABCA4 is acting as an importer of phospholipids and that mutations known to cause Stargardt disease decrease its activity.
- Faraz Quazi
- , Stepan Lenevich
- & Robert S. Molday
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| Open AccessDecreased extra-renal urate excretion is a common cause of hyperuricemia
Hyperuricemia, or gout, is thought to arise either from urate overproduction or from decreased renal excretion of urate. Ichidaet al. show that the extra-renal excretion of urate also has a role in the pathogenesis of hyperuricemia, and propose a new classification for patients with this disease.
- Kimiyoshi Ichida
- , Hirotaka Matsuo
- & Hiroshi Suzuki