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Frew JW
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Complement, hidradenitis suppurativa and pathogen-driven positive selection

BRITISH JOURNAL OF DERMATOLOGY 2019 MAR; 180(3):685-686
Linked Article: Kanni et al. Br J Dermatol 2018; 179:413-19.
Lara P, Tellgren-Roth A, Behesti H, Horn Z, Schiller N, Enquist K, Cammenberg M, Liljenstrom A, Hatten ME, von Heijne G, Nilsson I
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Murine astrotactins 1 and 2 have a similar membrane topology and mature via endoproteolytic cleavage catalyzed by a signal peptidase

JOURNAL OF BIOLOGICAL CHEMISTRY 2019 MAR 22; 294(12):4538-4545
Astrotactin 1 (Astn1) and Astn2 are membrane proteins that function in glial-guided migration, receptor trafficking, and synaptic plasticity in the brain as well as in planar polarity pathways in the skin. Here we used glycosylation mapping and protease protection approaches to map the topologies of mouse Astn1 and Astn2 in rough microsomal membranes and found that Astn2 has a cleaved N-terminal signal peptide, an N-terminal domain located in the lumen of the rough microsomal membranes (topologically equivalent to the extracellular surface in cells), two transmembrane helices, and a large C-terminal lumenal domain. We also found that Astn1 has the same topology as Astn2, but we did not observe any evidence of signal peptide cleavage in Astn1. Both Astn1 and Astn2 mature through endoproteolytic cleavage in the second transmembrane helix; importantly, we identified the endoprotease responsible for the maturation of Astn1 and Astn2 as the endoplasmic reticulum signal peptidase. Differences in the degree of Astn1 and Astn2 maturation possibly contribute to the higher levels of the C-terminal domain of Astn1 detected on neuronal membranes of the central nervous system. These differences may also explain the distinct cellular functions of Astn1 and Astn2, such as in membrane adhesion, receptor trafficking, and planar polarity signaling.
Boisson B, Honda Y, Ajiro M, Bustamante J, Bendavid M, Gennery AR, Kawasaki Y, Ichishima J, Osawa M, Nihira H, Shiba T, Tanaka T, Chrabieh M, Bigio B, Hur H, Itan Y, Liang YP, Okada S, Izawa K, Nishikomori R, Ohara O, Heike T, Abel L, Puel A, Saito MK, Casanova JL, Hagiwara M, Yasumi T
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Rescue of recurrent deep intronic mutation underlying cell type-dependent quantitative NEMO deficiency

JOURNAL OF CLINICAL INVESTIGATION 2019 FEB 1; 129(2):583-597
X-linked dominant incontinentia pigmenti (IP) and X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) are caused by loss-of-function and hypomorphic IKBKG (also known as NEMO) mutations, respectively. We describe a European mother with mild IP and a Japanese mother without IP, whose 3 boys with EDA-ID died from ID. We identify the same private variant in an intron of IKBKG, IVS4+866 C>T, which was inherited from and occurred de novo in the European mother and Japanese mother, respectively. This mutation creates a new splicing donor site, giving rise to a 44-nucleotide pseudoexon (PE) generating a frameshift. Its leakiness accounts for NF-kappa B activation being impaired but not abolished in the boys' cells. However, aberrant splicing rates differ between cell types, with WT NEMO mRNA and protein levels ranging from barely detectable in leukocytes to residual amounts in induced pluripotent stem cell-derived (iPSC-derived) macrophages, and higher levels in fibroblasts and iPSC-derived neuronal precursor cells. Finally, SRSF6 binds to the PE, facilitating its inclusion. Moreover, SRSF6 knockdown or CLK inhibition restores WT NEMO expression and function in mutant cells. A recurrent deep intronic splicing mutation in IKBKG underlies a purely quantitative NEMO defect in males that is most severe in leukocytes and can be rescued by the inhibition of SRSF6 or CLK.
Mann N, Braun DA, Amann K, Tan WZ, Shril S, Connaughton DM, Nakayama M, Schneider R, Kitzler TM, van der Ven AT, Chen J, Ityel H, Vivante A, Majmundar AJ, Daga A, Warejko JK, Lovric S, Ashraf S, Jobst-Schwan T, Widmeier E, Hugo H, Mane SM, Spaneas L, Somers MJG, Ferguson MA, Traum AZ, Stein DR, Baum MA, Daouk GH, Lifton RP, Manzi S, Vakili K, Kim HB, Rodig NM, Hildebrandt F
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Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 2019 FEB; 30(2):201-215
Background Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of amolecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. Methods To determine the diagnostic yield ofWES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children's Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. Results By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroidresistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WESrelated molecular genetic diagnosis had implications for clinical care for five patients. Conclusions Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.
LaCava J
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RNA Binding Proteins as Regulators of Retrotransposon-Induced Exonization

BIOESSAYS 2019 FEB; 41(2):? Article 1800263
Malik K, He H, Huynh TN, Tran G, Mueller K, Doytcheva K, Renert-Yuval Y, Czarnowicki T, Magidi S, Chou M, Estrada YD, Wen HC, Peng XY, Xu H, Zheng XZ, Krueger JG, Paller AS, Guttman-Yassky E
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Ichthyosis molecular fingerprinting shows profound T(H)17 skewing and a unique barrier genomic signature

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2019 FEB; 143(2):604-618
Background: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. Objective: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. Methods: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). Results: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-alpha-coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with T(H)1/IFN-gamma, OASL, and T(H)2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17-regulated gene expression (IL17F and IL36A/IL36B/IL36G). Conclusion: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36-targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.
Knorr DA, Ravetch JV
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Immunotherapy and Hyperprogression: Unwanted Outcomes, Unclear Mechanism

CLINICAL CANCER RESEARCH 2019 FEB 1; 25(3):904-906
Hyperprogression (HP) is a recently defined clinical phenomenon in which patients treated with immunotherapy paradoxically exhibit rapid tumor growth. The mechanisms of hyperprogression remain ill-defined, although recent studies in this issue point to a possible role for Fc receptors in this process.
Zhang L, Peng P, Wu YM, Ma XM, Soe NN, Huang XJ, Wu H, Markowitz M, Meyers K
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Modelling the Epidemiological Impact and Cost-Effectiveness of PrEP for HIV Transmission in MSM in China

AIDS AND BEHAVIOR 2019 FEB; 23(2):523-533
Risk of HIV infection is high in Chinese MSM, with an annual HIV incidence ranging from 3.41 to 13.7/100 person-years. Tenofovir-based PrEP is effective in preventing HIV transmission in MSM. This study evaluates the epidemiological impact and cost-effectiveness of implementing PrEP in Chinese MSM over the next two decades. A compartmental model for HIV was used to forecast the impact of PrEP on number of infections, deaths, and disability-adjusted life years (DALY) averted. We also provide an estimate of the incremental cost-effectiveness ratio (ICER) and the cost per DALY averted of the intervention. Without PrEP, there will be 1.1-3.0 million new infections and 0.7-2.3 million HIV-related deaths in the next two decades. Moderate PrEP coverage (50%) would prevent 0.17-0.32 million new HIV infections. At Truvada's current price in China, daily oral PrEP costs $46,813-52,008 per DALY averted and is not cost-effective; on-demand Truvada reduces ICER to $25,057-27,838 per DALY averted, marginally cost-effective; daily generic tenofovir-based regimens further reduce ICER to $3675-8963, wholly cost-effective. The cost of daily oral Truvada PrEP regimen would need to be reduced by half to achieve cost-effectiveness and realize the public health good of preventing hundreds of thousands of HIV infections among MSM in China.
Park D, Park SH, Kim YS, Choi BS, Kim JK, Kim NS, Choi IY
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NGS sequencing reveals that many of the genetic variations in transgenic rice plants match the variations found in natural rice population

GENES & GENOMICS 2019 FEB; 41(2):213-222
BackgroundAs the transformation process can induce mutations in host plants, molecular characterization of the associated genomic changes is important not only for practical food safety but also for understanding the fundamental theories of genome evolution.ObjectivesTo investigate a population-scale comparative study of the genome-wide spectrum of sequence variants in the transgenic genome with the variations present in 3000 rice varieties.ResultsOn average, we identified 19,273 SNPs (including Indels) per transgenic line in which 10,729 SNPs were at the identical locations in the three transgenic rice plants. We found that these variations were predominantly present in specific regions in chromosomes 8 and 10. Majority (88%) of the identified variations were detected at the same genomic locations as those in natural rice population, implying that the transgenic induced mutations had a tendency to be common alleles.ConclusionGenomic variations in transgenic rice plants frequently occurred at the same sites as the major alleles found in the natural rice population, which implies that the sequence variations occur within the limits of a biological system to ensure survival.
Shabani M, Aleyasin S, Kashef S, Zoghi S, Deswarte C, Casanova JL, Bustamante J, Rezaei N
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A Novel Recessive Mutation of Interferon- Receptor 1 in a Patient with Mycobacterium tuberculosis in Bone Marrow Aspirate

JOURNAL OF CLINICAL IMMUNOLOGY 2019 FEB; 39(2):127-130