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Genetics
Cryptococcus deuterogattii VGIIa Infection Associated with Travel to the Pacific Northwest Outbreak Region in an Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibody-Positive Patient in the United States.
Feb 13, 2019   MBio
Applen Clancey S, Ciccone EJ, Coelho MA, Davis J, Ding L, Betancourt R, Glaubiger S, Lee Y, Holland SM, Gilligan P, Sung J, Heitman J
Cryptococcus deuterogattii VGIIa Infection Associated with Travel to the Pacific Northwest Outbreak Region in an Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibody-Positive Patient in the United States.
Feb 13, 2019
MBio
The region encompassing the Pacific Northwest (PNW), Vancouver Island, Oregon, and Washington has been the location of an ongoing Cryptococcus gattii outbreak since the 1990s, and there is evidence that the outbreak is expanding along the West Coast into California. Here we report a clinical case of a 69-year-old, HIV-negative man from North Carolina who was diagnosed with a fungal brain mass by magnetic resonance imaging (MRI) and pathology. He had traveled to Seattle and Vancouver 3 years earlier and to Costa Rica 4 months prior to presentation. Phenotypic evidence showed that the fungal mass isolated from the patient's brain represented C. gattii In agreement with the phenotypic results, multilocus sequence typing (MLST) provided genotypic evidence that assigned the infecting organism within the C. gattii species complex and to the C. deuterogattii VGIIa clade. Whole-genome sequencing revealed >99.99% identity with the C. deuterogattii reference strain R265, indicating that the infecting strain is derived from the highly clonal outbreak strains in the PNW. We conclude that the patient acquired the C. gattii infection during his travel to the region 3 years prior and that the infection was dormant for an extended period of time before causing disease. The patient tested positive for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, supporting earlier reports that implicate these autoantibodies as a risk factor associated with C. gattii infection.IMPORTANCE Mortality rates associated with C. gattii infections are estimated to be between 13% and 33%, depending on an individual's predisposition, and C. gattii has caused at least 39 deaths in the PNW region. There have been four other international travel cases reported in patients from Europe and Asia with travel history to the PNW, but this report describes the first North American traveler who acquired C. deuterogattii infection presenting within the United States and the first case of a C. deuterogattii outbreak infection associated with anti-GM-CSF autoantibodies. Early and accurate diagnoses are important for disease prevention and treatment and for control of infectious diseases. Continual reporting of C. deuterogattii infections is necessary to raise awareness of the ongoing outbreak in the PNW and to alert travelers and physicians to the areas of endemicity with potential risks.
Distinguishing three distinct biogeographic regions with an in-house developed 39-AIM-InDel panel and further admixture proportion estimation for Uyghurs.
Feb 13, 2019   Electrophoresis
Lan Q, Shen C, Jin X, Guo Y, Xie T, Chen C, Cui W, Fang Y, Yang G, Zhu B
Distinguishing three distinct biogeographic regions with an in-house developed 39-AIM-InDel panel and further admixture proportion estimation for Uyghurs.
Feb 13, 2019
Electrophoresis
In the forensic field, ancestry-informative markers showing remarkable allele frequency discrepancies can be useful in deducing the likely ancestral origin of a person or estimating the ancestry component proportions of admixed populations or individuals. Diallelic SNPs are genetic markers commonly used for ancestry inference, but the genotyping methods of SNPs fail to fulfil the demands of cost-effectiveness and simplicity of experimental manipulation. To overcome the limitations, a 39 ancestry-informative InDels multiplex panel was developed in the present study to perform ancestry assignment of individuals from three distinct biogeographic regions (African, European, East Asian). And in the panel design, we also attempted to incorporate AIM-InDels exhibiting frequency differences in Han, Uyghur and Tibetan populations into the multiplex assay, further expecting to provide valuable information for refining ancestry inference within Chinese populations. Statistical analyses were performed to estimate efficiency of this panel in clustering individuals from three continents mentioned above into their corresponding populations, which indicated potential of the panel in ancestry inference. Besides, we also estimated the ancestral component proportions of Uyghur group and STRUCTURE analysis revealed that Uyghurs from Urumchi city of northern Xinjiang exhibited a distinctly admixed pattern of East Asian and European ancestry components with a ratio of 49:44, reflecting the relatively higher East Asian ancestry components contribution in the gene pool of the Uyghur group. This article is protected by copyright. All rights reserved.
Haploinsufficiency of UNC13D increases the risk of lymphoma.
Feb 13, 2019   Cancer
Löfstedt A, Ahlm C, Tesi B, Bergdahl IA, Nordenskjöld M, Bryceson YT, Henter JI, Meeths M
Haploinsufficiency of UNC13D increases the risk of lymphoma.
Feb 13, 2019
Cancer
BACKGROUND: Experimental models have demonstrated that immune surveillance by cytotoxic lymphocytes can protect from spontaneous neoplasms and cancer. In humans, defective lymphocyte cytotoxicity is associated with the development of hemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome. However, to the best of the authors' knowledge, the degree to which human lymphocyte cytotoxicity protects from cancer remains unclear. In the current study, the authors examined the risk of lymphoma attributable to haploinsufficiency in a gene required for lymphocyte cytotoxicity. METHODS: The authors exploited a founder effect of an UNC13D inversion, which abolishes Munc13-4 expression and causes hemophagocytic lymphohistiocytosis in an autosomal recessive manner. Within 2 epidemiological screening programs in northern Sweden, an area demonstrating a founder effect of this specific UNC13D mutation, all individuals with a diagnosis of lymphoma (487 patients) and matched controls (1844 controls) were assessed using polymerase chain reaction for carrier status. RESULTS: Among 487 individuals with lymphoma, 15 (3.1%) were heterozygous carriers of the UNC13D inversion, compared with 18 controls (1.0%) (odds ratio, 3.0; P = .002). It is interesting to note that a higher risk of lymphoma was attributed to female carriers (odds ratio, 3.7; P = .004). CONCLUSIONS: Establishing a high regional prevalence of the UNC13D inversion, the authors have reported an overrepresentation of this mutation in individuals with lymphoma. Therefore, the results of the current study indicate that haploinsufficiency of a gene required for lymphocyte cytotoxicity can predispose patients to lymphoma, suggesting the importance of cytotoxic lymphocyte-mediated surveillance of cancer. Furthermore, the results of the current study suggest that female carriers are more susceptible to lymphoma.
Single-Cell Allele-Specific Gene Expression Analysis.
Feb 13, 2019   Methods In Molecular Biology (Clifton, N.J.)
Dong M, Jiang Y
Single-Cell Allele-Specific Gene Expression Analysis.
Feb 13, 2019
Methods In Molecular Biology (Clifton, N.J.)
Allele-specific expression is traditionally studied by bulk RNA sequencing, which measures average gene expression across cells. Single-cell RNA sequencing (scRNA-seq) allows the comparison of expression distribution between the two alleles of a diploid organism, and characterization of allele-specific bursting. Here we describe SCALE, a bioinformatic and statistical framework for allele-specific gene expression analysis by scRNA-seq. SCALE estimates genome-wide bursting kinetics at the allelic level while accounting for technical bias and other complicating factors such as cell size. SCALE detects genes with significantly different bursting kinetics between the two alleles, as well as genes where the two alleles exhibit non-independent bursting processes. Here, we illustrate SCALE on a mouse blastocyst single-cell dataset with step-by-step demonstration from the upstream bioinformatic processing to the downstream biological interpretation of SCALE's output.
Transgenic Wucai (Brassica campestris L.) produced via Agrobacterium-mediated anther transformation in planta.
Feb 13, 2019   Plant Cell Reports
Chen G, Zeng F, Wang J, Ye X, Zhu S, Yuan L, Hou J, Wang C
Transgenic Wucai (Brassica campestris L.) produced via Agrobacterium-mediated anther transformation in planta.
Feb 13, 2019
Plant Cell Reports
KEY MESSAGE: We developed a novel Agrobacterium-mediated anther transformation for Wucai in planta, and in this procedure, the male germ line was the predominant target. Wucai (Brassica campestris L.), a variant of non-heading Chinese cabbage, is widely cultured in China and only improved by classic breeding methods. Here, a novel and efficient in planta Agrobacterium-mediated anther transformation method is developed based on the optimization of several factors that affect anther transformation. After optimization, transformation with the manual pollination application led to increased transient GUS expression in anthers (reaching 91.59%) and the transformation efficacies in planta (0.59-1.56% for four commercial cultivars). The stable integration and inheritance of the transgenes were further examined by molecular and genetic analyses. Three T2 transgenic lines presented a segregation ratio of 3:1, which was consistent with the Mendelian feature of a single dominant gene. In addition, the GUS histochemical assay and genetic crossing analysis revealed that the male germ line was the predominant target in this transformation. This optimized transformation system could provide a useful tool for both the improvement of cultivar qualities and investigation of functional genes in Wucai.
NUP214 deficiency causes severe encephalopathy and microcephaly in humans.
Feb 13, 2019   Human Genetics
Shamseldin HE, Makhseed N, Ibrahim N, Al-Sheddi T, Alobeid E, Abdulwahab F, Alkuraya FS
NUP214 deficiency causes severe encephalopathy and microcephaly in humans.
Feb 13, 2019
Human Genetics
Nuclear pore complex (NPC) is a fundamental component of the nuclear envelope and is key to the nucleocytoplasmic transport. Mutations in several NUP genes that encode individual components of NPC known as nucleoporins have been identified in recent years among patients with static encephalopathies characterized by developmental delay and microcephaly. We describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Autozygome and linkage analysis revealed that this phenotype is linked to a founder disease haplotype (chr9:127,113,732-135,288,807) in which whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214. Functional analysis of patient-derived fibroblasts recapitulated the dysmorphic phenotype of nuclei that was previously described in NUP214 knockdown cells. In addition, the typical rim staining of NUP214 is largely displaced, further supporting the deleterious effect of the variant. Our data expand the list of NUP genes that are mutated in encephalopathy disorders in humans.
[Genetics in neurology and psychiatry].
Feb 13, 2019   Der Nervenarzt
Rietschel M, Winkelmann J
[Breakthrough in understanding the molecular causes of psychiatric disorders].
Feb 13, 2019   Der Nervenarzt
Nöthen MM, Degenhardt F, Forstner AJ
[Breakthrough in understanding the molecular causes of psychiatric disorders].
Feb 13, 2019
Der Nervenarzt
A long-established hypothesis is that genetic factors contribute to the development of psychiatric diseases, including common illnesses such as schizophrenia and the affective disorders; however, reliable molecular identification of these factors represents a far more recent innovation. This has been rendered possible by technological advances in the individual characterization of the human genome and the combining of large genetic datasets at the international level. For the first time, the results of genome-wide analyses provide researchers with systematic insights into disease-relevant biological mechanisms. Here, the integrated analysis of different omics level data generates important insights into the functional interpretation of the genetic findings. The results of genetic studies also demonstrated the degree of etiological overlap between differing psychiatric disorders, with the greatest commonality having been observed to date between schizophrenia and bipolar affective disorder. Although the translation of genetic findings into routine clinical practice is being pursued at various levels, elaborate follow-up studies are typically necessary. The diagnostic investigation of rare genomic deletions/duplications (so-called copy number variants) in patients with schizophrenia is likely to represent one of the first examples of routine clinical application. The necessary prerequisites for this are currently being defined.
Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome With Life-Threatening Arrhythmias in Japanese Patients.
Feb 13, 2019   JAMA Cardiology
Shimizu W, Makimoto H, Yamagata K, Kamakura T, Wada M,   . . . . . .   , Aizawa Y, Makita N, Ohe T, Horie M, Aiba T
Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome With Life-Threatening Arrhythmias in Japanese Patients.
Feb 13, 2019
JAMA Cardiology
Importance: Long QT syndrome (LQTS) is caused by several ion channel genes, yet risk of arrhythmic events is not determined solely by the responsible gene pathogenic variants. Female sex after adolescence is associated with a higher risk of arrhythmic events in individuals with congenital LQTS, but the association between sex and genotype-based risk of LQTS is still unclear. Objective: To examine the association between sex and location of the LQTS-related pathogenic variant as it pertains to the risk of life-threatening arrhythmias. Design, Setting, and Participants: This retrospective observational study enrolled 1124 genotype-positive patients from 11 Japanese institutions from March 1, 2006, to February 28, 2013. Patients had LQTS type 1 (LQT1), type 2 (LQT2), and type 3 (LQT3) (616 probands and 508 family members), with KCNQ1 (n = 521), KCNH2 (n = 487) and SCN5A (n = 116) genes. Clinical characteristics such as age at the time of diagnosis, sex, family history, cardiac events, and several electrocardiographic measures were collected. Statistical analysis was conducted from January 18 to October 10, 2018. Main Outcomes and Measures: Sex difference in the genotype-specific risk of congenital LQTS. Results: Among the 1124 patients (663 females and 461 males; mean [SD] age, 20 [15] years) no sex difference was observed in risk for arrhythmic events among those younger than 15 years; in contrast, female sex was associated with a higher risk for LQT1 and LQT2 among those older than 15 years. In patients with LQT1, the pathogenic variant of the membrane-spanning site was associated with higher risk of arrhythmic events than was the pathogenic variant of the C-terminus of KCNQ1 (HR, 1.60; 95% CI, 1.19-2.17; P = .002), although this site-specific difference in the incidence of arrhythmic events was observed in female patients only. In patients with LQT2, those with S5-pore-S6 pathogenic variants in KCNH2 had a higher risk of arrhythmic events than did those with others (HR, 1.88; 95% CI, 1.44-2.44; P 
Architectural principles for Hfq/Crc-mediated regulation of gene expression.
Feb 13, 2019   ELife
Pei XY, Dendooven T, Sonnleitner E, Chen S, Blasi U, Luisi BF
Architectural principles for Hfq/Crc-mediated regulation of gene expression.
Feb 13, 2019
ELife
In diverse bacterial species, the global regulator Hfq contributes to post-transcriptional networks that control expression of numerous genes. Hfq of the opportunistic pathogen Pseudomonas aeruginosa inhibits translation of target transcripts by forming a regulatory complex with the catabolite repression protein Crc. This repressive complex acts part of an intricate mechanism of preferred nutrient utilisation. We describe high-resolution cryo-EM structures of the assembly of Hfq and Crc bound to the translation initiation site of a target mRNA. The core of the assembly is formed through interactions of two cognate RNAs, two Hfq hexamers and a Crc pair. Additional Crc protomers are recruited to the core to generate higher-order assemblies with demonstrated regulatory activity in vivo. This study reveals how Hfq cooperates with a partner protein to regulate translation, and provides a structural basis for an RNA code that guides global regulators to interact cooperatively and regulate different RNA targets.
Transcriptional Signatures Modulating SAM Morphometric and Plant Architectural Traits Enhance Yield and Productivity in Chickpea.
Feb 13, 2019   The Plant Journal : For Cell And Molecular Biology
Narnoliya L, Basu U, Bajaj D, Malik N, Thakro V, Daware A, Sharma A, Tripathi S, Hegde VS, Upadhyaya HD, Singh AK, Tyagi AK, Parida SK
Transcriptional Signatures Modulating SAM Morphometric and Plant Architectural Traits Enhance Yield and Productivity in Chickpea.
Feb 13, 2019
The Plant Journal : For Cell And Molecular Biology
Plant height (PH) and plant width (PW), two of the major plant architectural traits determining the yield and productivity of a crop, are defined by diverse morphometric characteristics of the shoot apical meristem (SAM). The identification of potential molecular tags from a single gene that simultaneously modulates these plant/SAM architectural traits is thus prerequisite to achieve enhanced yield and productivity in crop plants, including chickpea. Large-scale multi-environment phenotyping of the association panel and mapping population have ascertained the efficacy of three vital SAM morphometric trait parameters, SAM width, SAM height and SAM area, as key indicators to unravel the genetic basis of the wide PW and PH trait variations observed in desi chickpea. The present study integrated a genome-wide association study (GWAS); QTL/fine-mapping and map-based cloning with molecular haplotyping; transcript profiling; and protein-DNA interaction assays for the dissection of plant architectural traits in chickpea. These exertions delineated natural alleles and superior haplotypes from a CabHLH121 transcription factor (TF) gene within the major QTLs governing PW, PH and SAM morphometric traits. A genome-wide protein-DNA interaction assay assured the direct binding of a known stem cell master regulator, CaWUS, to the WOX-homeodomain TF binding sites of a CabHLH121 gene and its constituted haplotypes. The differential expression of CaWUS and transcriptional regulation of its target CabHLH121 gene/haplotypes were apparent, suggesting their collective role in altering SAM morphometric characteristics and plant architectural traits in the contrasting near isogenic lines (NILs). The NILs introgressed with a superior haplotype of a CabHLH121 exhibited optimal PW and desirable PH as well as enhanced yield and productivity without compromising any component of agronomic performance. These molecular signatures of the CabHLH121 TF gene have the potential to regulate both PW and PH traits through the modulation of proliferation, differentiation and maintenance of the meristematic stem cell population in the SAM; therefore, these signatures will be useful in the translational genomic study of chickpea genetic enhancement. The restructured cultivars with desirable PH (semi-dwarf) and PW will ensure maximal planting density in a specified cultivable field area, thereby enhancing the overall yield and productivity of chickpea. This can essentially facilitate the achievement of better remunerative outputs by farmers with rational land use, thus ensuring global food security in the present scenario of an increasing population density and shrinking per capita land area. This article is protected by copyright. All rights reserved.
Dissection of Merkel cell formation in hairy and glabrous skin reveals a common requirement for FGFR2-mediated signaling.
Feb 13, 2019   Experimental Dermatology
Nguyen MB, Valdes VJ, Cohen I, Pothula V, Zhao D, Zheng D, Ezhkova E
Dissection of Merkel cell formation in hairy and glabrous skin reveals a common requirement for FGFR2-mediated signaling.
Feb 13, 2019
Experimental Dermatology
Merkel cells are mechanosensory cells involved in tactile discrimination. Merkel cells have been primarily studied in the murine back skin, where they are found in specialized structures called touch domes located around primary hair follicles. Yet, little is known about the morphogenesis of Merkel cells in areas of the skin devoid of hair, such as the glabrous paw skin. Here, we describe Merkel cell formation in the glabrous paw skin during embryogenesis. We first found in the glabrous paw skin that Merkel cells were specified at E15.5, 24 hours later, compared to in the back skin. Additionally, by performing lineage-tracing experiments, we found that unlike in the back skin, SOX9(+) cells do not give rise to Merkel cells in the glabrous paw skin. Finally, we compared the transcriptomes of Merkel cells in the back and the glabrous paw skin and showed that they are similar. Genetic and transcriptome studies showed that the formation of Merkel cells in both regions was controlled by similar regulators. Among them was FGFR2, an upstream factor of MAPK signaling that was reported to have a critical function in Merkel cell formation in the back skin. Here, we showed that FGFR2 is also required for Merkel cell development in the glabrous paw skin. Taken together, our results demonstrate that Merkel cells in the murine back skin and glabrous paw skin are similar, and even though their formation is controlled by a common genetic program, their precursor cells might differ. This article is protected by copyright. All rights reserved.
Oophorectomy and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers.
Feb 13, 2019   Breast Cancer Research And Treatment
Kotsopoulos J, Lubinski J, Lynch HT, Tung N, Armel S,   . . . . . .   , Olopade O, Sun P, Gronwald J, Narod SA, Hereditary Breast Cancer Clinical Study Group
Oophorectomy and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers.
Feb 13, 2019
Breast Cancer Research And Treatment
PURPOSE: Following a diagnosis of breast cancer, BRCA mutation carriers face an increased risk of developing a second (contralateral) cancer in the unaffected breast. It is important to identify predictors of contralateral cancer in order to make informed decisions about bilateral mastectomy. The impact of bilateral salpingo-oophorectomy (i.e., oophorectomy) on the risk of developing contralateral breast cancer is unclear. Thus, we conducted a prospective study of the relationship between oophorectomy and the risk of contralateral breast cancer in 1781 BRCA1 and 503 BRCA2 mutation carriers with breast cancer. METHODS: Women were followed from the date of diagnosis of their first breast cancer until the date of diagnosis of a contralateral breast cancer, bilateral mastectomy, date of death, or date of last follow-up. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of contralateral breast cancer associated with oophorectomy. Oophorectomy was included as a time-dependent covariate. We performed a left-censored analysis for those women who reported a primary breast cancer prior to study entry (i.e., from completion of baseline questionnaire). RESULTS: After an average of 9.8 years of follow-up, there were 179 (7.8%) contralateral breast cancers diagnosed. Oophorectomy was not associated with the risk of developing a second breast cancer (HR 0.92; 95% CI 0.68-1.25). The relationship did not vary by BRCA mutation type or by age at diagnosis of the first breast cancer. There was some evidence for a decreased risk of contralateral breast cancer among women with an ER-positive primary breast cancer, but this was based on a small number of events (n = 240). CONCLUSION: Overall, our findings suggest that oophorectomy has little impact on the risk of contralateral breast cancer.
PILS6 is a temperature-sensitive regulator of nuclear auxin input and organ growth in Arabidopsis thaliana.
Feb 13, 2019   Proceedings Of The National Academy Of Sciences Of The United States Of America
Feraru E, Feraru MI, Barbez E, Waidmann S, Sun L, Gaidora A, Kleine-Vehn J
PILS6 is a temperature-sensitive regulator of nuclear auxin input and organ growth in Arabidopsis thaliana.
Feb 13, 2019
Proceedings Of The National Academy Of Sciences Of The United States Of America
Temperature modulates growth and development throughout the entire lifecycle of a plant. High temperature (HT) triggers the auxin biosynthesis-dependent growth in aerial tissues. On the other hand, the contribution of auxin to HT-induced root growth is currently under debate. Here we show that the putative intracellular auxin carrier PIN-LIKES 6 (PILS6) is a negative regulator of organ growth and that its abundance is highly sensitive to HT. PILS6 localizes to the endoplasmic reticulum and limits the nuclear availability of auxin, consequently reducing the auxin signaling output. HT represses the PILS6 protein abundance, which impacts on PILS6-dependent auxin signaling in roots and root expansion. Accordingly, we hypothesize that PILS6 is part of an alternative mechanism linking HT to auxin responses in roots.
Expression of a novel PSK-encoding gene from soybean improves seed growth and yield in transgenic plants.
Feb 13, 2019   Planta
Yu L, Liu Y, Zeng S, Yan J, Wang E, Luo L
Expression of a novel PSK-encoding gene from soybean improves seed growth and yield in transgenic plants.
Feb 13, 2019
Planta
MAIN CONCLUSION: Expression of GmPSKγ1 , a novel PSK-encoding gene from soybean, increases seed size and yield in transgenic plants by promoting cell expansion. Phytosulfokine-α (PSK-α), a sulfated pentapeptide hormone with the sequence YIYTQ, plays important roles in many aspects of plant growth and development. In this study, we identified a pair of putative precursor genes in soybean, GmPSKγ1 and -2, encoding a PSK-like peptide: PSK-γ. Similar to PSK-α in amino acid composition, the sequence of PSK-γ is YVYTQ, and the tyrosines undergo sulfonylation. Treatment of Arabidopsis seedlings with synthetic sulfated PSK-γ significantly enhanced root elongation, indicating that PSK-γ might be a functional analog of PSK-α. Expression pattern analysis revealed that the two GmPSKγ genes, especially GmPSKγ1, are primarily expressed in developing soybean seeds. Heterologous expression of GmPSKγ1 under the control of a seed-specific promoter markedly increased seed size and weight in Arabidopsis, and this promoting effect of PSK-γ on seed growth was further confirmed in transgenic tobacco constitutively expressing GmPSKγ1. Cytological analysis of transgenic Arabidopsis seeds revealed that PSK-γ promotes seed growth by inducing embryo cell expansion. In addition, expression analysis of downstream candidate genes suggested that PSK-γ signaling might regulate cell wall loosening to promote cell expansion in Arabidopsis seeds. Overall, our results shed light on the mechanism by which PSK-γ promotes seed growth, paving the way for the use of this new peptide for biotechnological improvement of crop seed/grain size and yield.
Rare Inherited forms of Paget's Disease and Related Syndromes.
Feb 13, 2019   Calcified Tissue International
Ralston SH, Taylor JP
Rare Inherited forms of Paget's Disease and Related Syndromes.
Feb 13, 2019
Calcified Tissue International
Several rare inherited disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB) and in which PDB is a component of a multisystem disorder affecting muscle and the central nervous system. These conditions are the subject of this review article. Insertion mutations within exon 1 of the TNFRSF11A gene, encoding the receptor activator of nuclear factor kappa B (RANK), cause severe PDB-like disorders including familial expansile osteolysis, early-onset familial PDB and expansile skeletal hyperphosphatasia. The mutations interfere with normal processing of RANK and cause osteoclast activation through activation of nuclear factor kappa B (NFκB) independent of RANK ligand stimulation. Recessive, loss-of-function mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB and here the bone disease is due to unopposed activation of RANK by RANKL. Multisystem proteinopathy is a disorder characterised by myopathy and neurodegeneration in which PDB is often an integral component. It may be caused by mutations in several genes including VCP, HNRNPA1, HNRNPA2B1, SQSTM1, MATR3, and TIA1, some of which are involved in classical PDB. The mechanisms of osteoclast activation in these conditions are less clear but may involve NFκB activation through sequestration of IκB. The evidence base for management of these disorders is somewhat limited due to the fact they are extremely rare. Bisphosphonates have been successfully used to gain control of elevated bone remodelling but as yet, no effective treatment exists for the treatment of the muscle and neurological manifestations of MSP syndromes.
Genomic annotation of disease-associated variants reveals shared functional contexts.
Feb 13, 2019   Diabetologia
Kyono Y, Kitzman JO, Parker SCJ
Genomic annotation of disease-associated variants reveals shared functional contexts.
Feb 13, 2019
Diabetologia
Variation in non-coding DNA, encompassing gene regulatory regions such as enhancers and promoters, contributes to risk for complex disorders, including type 2 diabetes. While genome-wide association studies have successfully identified hundreds of type 2 diabetes loci throughout the genome, the vast majority of these reside in non-coding DNA, which complicates the process of determining their functional significance and level of priority for further study. Here we review the methods used to experimentally annotate these non-coding variants, to nominate causal variants and to link them to diabetes pathophysiology. In recent years, chromatin profiling, massively parallel sequencing, high-throughput reporter assays and CRISPR gene editing technologies have rapidly become indispensable tools. Rather than treating individual variants in isolation, we discuss the importance of accounting for context, both genetic (such as flanking DNA sequence) and environmental (such as cellular state or environmental exposure). Incorporating these features shows promise in terms of revealing biologically convergent molecular signatures across distant and seemingly unrelated loci. Studying regulatory elements in the proper context will be crucial for interpreting the functional significance of disease-associated variants and applying the resulting knowledge to improve patient care.
CFP suppresses breast cancer cell growth by TES-mediated upregulation of the transcription factor DDIT3.
Feb 13, 2019   Oncogene
Block I, Müller C, Sdogati D, Pedersen H, List M,   . . . . . .   , Thomassen M, Kruse TA, Karlskov Hansen SW, Kioschis P, Mollenhauer J
CFP suppresses breast cancer cell growth by TES-mediated upregulation of the transcription factor DDIT3.
Feb 13, 2019
Oncogene
Breast cancer is a heterogeneous genetic disease driven by the accumulation of individual mutations per tumor. Whole-genome sequencing approaches have identified numerous genes with recurrent mutations in primary tumors. Although mutations in well characterized tumor suppressors and oncogenes are overrepresented in these sets, the majority of the genetically altered genes have so far unknown roles in breast cancer progression. To improve the basic understanding of the complex disease breast cancer and to potentially identify novel drug targets or regulators of known cancer-driving pathways, we analyzed 86 wild-type genes and 94 mutated variants for their effect on cell growth using a serially constructed panel of MCF7 cell lines. We demonstrate in subsequent experiments that the metal cation transporter CNNM4 regulates growth by induction of apoptosis and identified a tumor suppressive role of complement factor properdin (CFP) in vitro and in vivo. CFP appears to induce the intracellular upregulation of the pro-apoptotic transcription factor DDIT3 which is associated with endoplasmic reticulum-stress response.
The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy.
Feb 13, 2019   Nature Reviews. Cancer
Havel JJ, Chowell D, Chan TA
The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy.
Feb 13, 2019
Nature Reviews. Cancer
Checkpoint inhibitor-based immunotherapies that target cytotoxic T lymphocyte antigen 4 (CTLA4) or the programmed cell death 1 (PD1) pathway have achieved impressive success in the treatment of different cancer types. Yet, only a subset of patients derive clinical benefit. It is thus critical to understand the determinants driving response, resistance and adverse effects. In this Review, we discuss recent work demonstrating that immune checkpoint inhibitor efficacy is affected by a combination of factors involving tumour genomics, host germline genetics, PD1 ligand 1 (PDL1) levels and other features of the tumour microenvironment, as well as the gut microbiome. We focus on recently identified molecular and cellular determinants of response. A better understanding of how these variables cooperate to affect tumour-host interactions is needed to optimize the implementation of precision immunotherapy.
Fibroblast growth factor receptor signaling in pediatric B-cell precursor acute lymphoblastic leukemia.
Feb 16, 2019   Scientific Reports
Jerchel IS, Hoogkamer AQ, Ariës IM, Boer JM, Besselink NJM, Koudijs MJ, Pieters R, den Boer ML
Fibroblast growth factor receptor signaling in pediatric B-cell precursor acute lymphoblastic leukemia.
Feb 16, 2019
Scientific Reports
The FGF receptor signaling pathway is recurrently involved in the leukemogenic processes. Oncogenic fusions of FGFR1 with various fusion partners were described in myeloid proliferative neoplasms, and overexpression and mutations of FGFR3 are common in multiple myeloma. In addition, fibroblast growth factors are abundant in the bone marrow, and they were shown to enhance the survival of acute myeloid leukemia cells. Here we investigate the effect of FGFR stimulation on pediatric BCP-ALL cells in vitro, and search for mutations with deep targeted next-generation sequencing of mutational hotspots in FGFR1, FGFR2, and FGFR3. In 481 primary BCP-ALL cases, 28 samples from 19 unique relapsed BCP-ALL cases, and twelve BCP-ALL cell lines we found that mutations are rare (4/481 = 0.8%, 0/28 and 0/12) and do not affect codons which are frequently mutated in other malignancies. However, recombinant ligand FGF2 reduced the response to prednisolone in several BCP-ALL cell lines in vitro. We therefore conclude that FGFR signaling can contribute to prednisolone resistance in BCP-ALL cells, but that activating mutations in this receptor tyrosine kinase family are very rare.
Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.
Feb 16, 2019   Nature Communications
Siekierska A, Stamberger H, Deconinck T, Oprescu SN, Partoens M,   . . . . . .   , Weckhuysen S, Francklyn C, Antonellis A, de Witte P, De Jonghe P
Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.
Feb 16, 2019
Nature Communications
Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.
Publisher Correction: Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis.
Feb 16, 2019   Nature Communications
Wei Z, Song J, Wang G, Cui X, Zheng J, Tang Y, Chen X, Li J, Cui L, Liu CY, Yu W
Publisher Correction: Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis.
Feb 16, 2019
Nature Communications
The original version of this Article contained an error in the Data Availability Statement. The accession code indicated '53V' and should have read '5X3V'. This has been corrected in both PDF and HTML versions of the Article.
Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.
Feb 16, 2019   Nature Communications
Friedman J, Smith DE, Issa MY, Stanley V, Wang R,   . . . . . .   , Kingsmore SF, Salomons GS, Zaki MS, Bernard G, Gleeson JG
Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.
Feb 16, 2019
Nature Communications
Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.
Reply to Liu et al.: Tissue specificity of SIM1 gene expression and erectile dysfunction.
Feb 13, 2019   Proceedings Of The National Academy Of Sciences Of The United States Of America
Jorgenson E, Matharu N, Palmer MR, Yin J, Shan J, Hoffmann TJ, Thai KK, Zhou X, Hotaling JM, Jarvik GP, Ahituv N, Wessells H, Van Den Eeden SK
ERF-related craniosynostosis: The phenotypic and developmental profile of a new craniosynostosis syndrome.
Feb 13, 2019   American Journal Of Medical Genetics. Part A
Glass GE, O'Hara J, Canham N, Cilliers D, Dunaway D,   . . . . . .   , Twigg SRF, Vasudevan P, Wall SA, Wilkie AOM, Wilson LC
ERF-related craniosynostosis: The phenotypic and developmental profile of a new craniosynostosis syndrome.
Feb 13, 2019
American Journal Of Medical Genetics. Part A
Mutations in the ERF gene, coding for ETS2 repressor factor, a member of the ETS family of transcription factors cause a recently recognized syndromic form of craniosynostosis (CRS4) with facial dysmorphism, Chiari-1 malformation, speech and language delay, and learning difficulties and/or behavioral problems. The overall prevalence of ERF mutations in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis. Here, we present findings from 16 unrelated probands with ERF-related craniosynostosis, with additional data from 20 family members sharing the mutations. Most of the probands exhibited multisutural (including pan-) synostosis but a pattern involving the sagittal and lambdoid sutures (Mercedes-Benz pattern) predominated. Importantly the craniosynostosis was often postnatal in onset, insidious and progressive with subtle effects on head morphology resulting in a median age at presentation of 42 months among the probands and, in some instances, permanent visual impairment due to unsuspected raised intracranial pressure (ICP). Facial dysmorphism (exhibited by all of the probands and many of the affected relatives) took the form of orbital hypertelorism, mild exorbitism and malar hypoplasia resembling Crouzon syndrome but, importantly, a Class I occlusal relationship. Speech delay, poor gross and/or fine motor control, hyperactivity and poor concentration were common. Cranial vault surgery for raised ICP and/or Chiari-1 malformation was expected when multisutural synostosis was observed. Variable expressivity and nonpenetrance among genetically affected relatives was encountered. These observations form the most complete phenotypic and developmental profile of this recently identified craniosynostosis syndrome yet described and have important implications for surgical intervention and follow-up.

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