| 1. |
- Berglund, Andreas, et al.
(författare)
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15 koncept för bättre ergonomi : Inom äldreomsorg, fysioterapi, däckmontering och varuhantering
- 2015
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Rapport (populärvet., debatt m.m.)abstract
- Den här boken är resultatet av en kurs i ergonomi vid Teknisk design, Luleå tekniska universitet, våren 2015. 15 kursdeltagare har under 10 veckor använt designmetodik och ergonomiska teorier och metoder för att utveckla 15 konceptuella förbättringsförslag baserade på de 4 undersökta kontexterna äldreomsorg, fysioterapi, däckmontering och varuhantering. Fokus för ergonomi inom området teknisk design är att se till att all design, oavsett vilket system det avser, kompletterar människans styrkor och förmågor. Vi ska kort och gott se till att arbetsuppgifter, utrustning, apparater, processer, miljöer och organisationer utformas med människan som utgångspunkt, istället för att tvinga människan att anpassa sig med olika former av överbelastning som möjlig påföljd. För att uppnå detta behöver vi förstå och designa för den variabilitet som är representerad bland oss människor: vi är olika, har olika åldrar, storlek, styrka, kognitiv förmåga, erfarenheter, förväntningar och mål. Att tillämpa ergonomi betyder att studera hur människor interagerar med produkter, processer, miljöer och system för att förbättra dem, dvs. göra dem enklare, säkrare, bekvämare och effektivare att använda. För att kunna göra det behöver vi kunskap om människans förutsättningar och behov. Teknisk design med utgångspunkt och mål i god ergonomi innebär att exempelvis: Att designa produkter och utrustning som är enkla och tillförlitliga att använda med utgångspunkt i kunskap om kognitiv ergonomi, antropometri och belastningsergonomiska och biomekaniska analyserAtt designa säkra och effektiva tillverkningsprocesser med utgångspunkt i kunskap om kognitiv ergonomi och belastningsergonomiska analyserAtt designa organisationer utifrån kunskap om arbetslivsfysiologi och organisationsergonomiAtt designa arbetsuppgifter utifrån kunskap om kognitiv ergonomi, biomekanik och belastningsergonomiska analyserAtt designa enkla och användarvänliga gränssnitt med utgångspunkt i kognitiv ergonomiErgonomisk anpassning av en produkt eller en arbetsmiljö kan exempelvis handla om att se till att människan inte använder kroppen felaktigt. Det kan handla om fysisk belastning när en uppgift utförs, såväl som sensorisk input från olika system eller psykosocial belastning i form av stress. Det handlar om att utveckla kunskaper om människans begränsningar och förmågor, vilket ger bättre förutsättningar att bidra till användarvänliga lösningar. Det i sin tur bidrar till säkerhet och användarvänlighet och i slutändan att alla produkter, system och miljöer i vår omvärld fungerar väl för människan – det är hållbar utveckling om något. I kursen Ergonomi 2 vid civilingenjörsutbildningen Teknisk design, Luleå tekniska universitet, ingår en projektuppgift. Den syftar till att få fördjupad förståelse inom ergonomi genom att tillämpa kunskap och metoder i ett designprojekt för en verklig situation. Våren 2015 omfattade projektuppgiften att enanalys av valfri kontext, med syfte att förstå problem och utmaningar i den miljö, det sammanhang, den situation och för de personer som var berörda. Inledningsvis arbetade kursdeltagarna i grupper bestående av 3-4 personer, för att sedan gå in i en konceptutvecklingsfas individuellt. Det innebar att kursdeltagarna kunde genomföra ergonomiska analyser gemensamt och sedan utveckla konceptuella lösningar på egen hand. Det resulterade i att kursdeltagarna utvecklade tämligen olika lösningar, även om de haft en gemensam utgångspunkt. Bokens kapitel omfattar en beskrivning av respektive kontext följt av de konceptförslag som kursdeltagarna utvecklade. Som lärare är det alltid extra roligt när kursdeltagare är motiverade och engagerade inför projektuppgifter. Vår förhoppning är att det engagemanget ska framgå på följande sidor och att koncepten ska ge inspiration till att förbättra ergonomin i våra vardagsliv. Åsa Wikberg Nilsson, Therese Öhrling, Lars Sundström, Agneta Larsson och Ulrik RöijezonTeknisk design Luleå tekniska universitet, Augusti 2015
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| 2. |
- Högström, Sofie, et al.
(författare)
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Dance and Yoga Reduced Functional Abdominal Pain in Young Girls : A Randomized Controlled Trial
- 2022
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Ingår i: European Journal of Pain. - : John Wiley & Sons. - 1090-3801 .- 1532-2149. ; 26:2, s. 336-348
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Tidskriftsartikel (refereegranskat)abstract
- Background: Functional abdominal pain disorders (FAPDs) affect children, especially girls, all over the world. The evidence for existing treatments is mixed, and effective accessible treatments are needed. Dance, a rhythmic cardio-respiratory activity, combined with yoga, which enhances relaxation and focus, may provide physiological and psychological benefits that could help to ease pain.Objectives: The aim with this study was to evaluate the effects of a dance and yoga intervention on maximum abdominal pain in 9- to 13-year- old girls with FAPDs.Methods: This study was a prospective randomised controlled trial with 121 participants recruited from outpatient clinics as well as the general public. The intervention group participated in dance and yoga twice weekly for 8 months; controls received standard care. Abdominal pain, as scored on the Faces Pain Scale–Revised, was recorded in a pain diary. A linear mixed model was used to estimate the outcomes and effect sizes.Results: Dance and yoga were superior to standard healthcare alone, with a medium to high between-group effect size and significantly greater pain reduction (b = −1.29, p = 0.002) at the end of the intervention.Conclusions: An intervention using dance and yoga is likely a feasible and beneficial complementary treatment to standard health care for 9- to 13-year-old girls with FAPDs.Significance: FAPDs affect children, especially girls, all over the world. The negative consequences such as absence from school, high consumption of medical care and depression pose a considerable burden on children and their families and effective treatments are needed. This is the first study examining a combined dance/yoga intervention for young girls with FAPDs and the result showed a reduction of abdominal pain. These findings contribute with new evidence in the field of managing FAPDs in a vulnerable target group.
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Cederkrantz, Elin, et al.
(författare)
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Evaluation of Effects on the Peritoneum After Intraperitoneal α-Radioimmunotherapy with (211)At.
- 2012
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 27:6, s. 353-364
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Tidskriftsartikel (refereegranskat)abstract
- Abstract The introduction of the short-lived α-emitter (211)At to intraperitoneal radioimmunotherapy has raised the issue of the tolerance dose of the peritoneum. The short range of the α-particles (70μm) and the short half-life (7.21h) of the nuclide yield a dose distribution in which the peritoneum is highly irradiated compared with other normal tissues. To address this issue, mice were injected with (211)At-trastuzumab to irradiate the peritoneum to absorbed doses ranging between 0 and 50 Gy and followed for up to 34 weeks. The peritoneum-to-plasma clearance of a small tracer, (51)Cr-ethylenediamine tetraacetic acid, was measured for evaluation of the small solute transport capacity of the peritoneal membrane. The macroscopic status of the peritoneum and the mesenteric windows was documented when the mice were sacrificed. Biopsies of the peritoneum were taken for morphology and immunohistochemical staining against plasminogen activator inhibitor-1 and calprotectin. Peritoneum-to-plasma clearance measurements indicated a dose-dependent decrease in peritoneal transport capacity in irradiated mice. However, macroscopic and microscopic evaluations of the peritoneal membrane showed no difference between irradiated mice versus controls. The results imply that the peritoneal membrane tolerates absorbed doses as high as 30-50 Gy from α-particle irradiation with limited response.
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| 7. |
- de Miranda, Noel F. C. C., et al.
(författare)
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DNA repair genes are selectively mutated in diffuse large B cell lymphomas
- 2013
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 210:9, s. 1729-1742
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Tidskriftsartikel (refereegranskat)abstract
- DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.
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| 8. |
- Falk, Elin
(författare)
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Reseminnen och reformtankar
- 1907
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Bok (populärvet., debatt m.m.)abstract
- Intryck från Elin Falks resa i Schweiz, Tyskland och Danmark 1907, där hon studerade hur gymnastik och kroppsövningar tillämpas.
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| 9. |
- Johansson, Henrik, et al.
(författare)
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Targeted resequencing of candidate genes using Selector Probes
- 2011
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 39:2, s. e8-
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Tidskriftsartikel (refereegranskat)abstract
- Targeted genome enrichment is a powerful tool for making use of the massive throughput of novel DNA-sequencing instruments. We herein present a simple and scalable protocol for multiplex amplification of target regions based on the Selector technique. The updated version exhibits improved coverage and compatibility with next-generation-sequencing (NGS) library-construction procedures for shotgun sequencing with NGS platforms. To demonstrate the performance of the technique, all 501 exons from 28 genes frequently involved in cancer were enriched for and sequenced in specimens derived from cell lines and tumor biopsies. DNA from both fresh frozen and formalin-fixed paraffin-embedded biopsies were analyzed and 94 specificity and 98 coverage of the targeted region was achieved. Reproducibility between replicates was high (R 2=0, 98) and readily enabled detection of copy-number variations. The procedure can be carried out in <24 h and does not require any dedicated instrumentation.
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| 10. |
- La Fleur, Linnea, et al.
(författare)
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Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11
- 2019
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 130, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.
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| 11. |
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| 12. |
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| 13. |
- Lundin, Karin E, et al.
(författare)
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Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene
- 2015
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Ingår i: Clinical Immunology. - : Elsevier. - 1521-6616 .- 1521-7035. ; 161:2, s. 366-372
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Tidskriftsartikel (refereegranskat)abstract
- Phosphoglucomutase 3 (PGM3) is an enzyme converting N-acetyl-glucosamine-6-phosphate to N-acetylglucosamine-l-phosphate, a precursor important for glycosylation. Mutations in the PGM3 gene have recently been identified as the cause of novel primary immunodeficiency with a hyper-IgE like syndrome. Here we report the occurrence of a homozygous mutation in the PGM3 gene in a family with immunodeficient children, described already in 1976. DNA from two of the immunodeficient siblings was sequenced and shown to encode the same homozygous missense mutation, causing a destabilized protein with reduced enzymatic capacity. Affected individuals were highly prone to infections, but lack the developmental defects in the nervous and skeletal systems, reported in other families. Moreover, normal IgE levels were found. Thus, belonging to the expanding group of congenital glycosylation defects, PGM3 deficiency is characterized by immunodeficiency, with or without increased IgE levels, and with variable forms of developmental defects affecting other organ systems.
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| 14. |
- Mansouri, Larry, et al.
(författare)
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Functional loss of I kappa B epsilon leads to NF-kappa B deregulation in aggressive chronic lymphocytic leukemia
- 2015
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 212:6, s. 833-843
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Tidskriftsartikel (refereegranskat)abstract
- NF-kappa B is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-kappa B pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes I kappa B epsilon, a negative regulator of NF-kappa B in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced I kappa B epsilon protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that I kappa B epsilon loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-kappa B deregulation during lymphomagenesis.
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| 15. |
- Mansouri, Larry, et al.
(författare)
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Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia.
- 2015
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 212:6, s. 833-843
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Tidskriftsartikel (refereegranskat)abstract
- NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.
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| 16. |
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| 17. |
- Mathot, Lucy, et al.
(författare)
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Automated Genotyping of Biobank Samples by Multiplex Amplification of Insertion/Deletion Polymorphisms
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:12
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Tidskriftsartikel (refereegranskat)abstract
- The genomic revolution in oncology will entail mutational analyses of vast numbers of patient-matched tumor and normal tissue samples. This has meant an increased risk of patient sample mix up due to manual handling. Therefore, scalable genotyping and sample identification procedures are essential to pathology biobanks. We have developed an efficient alternative to traditional genotyping methods suited for automated analysis. By targeting 53 prevalent deletions and insertions found in human populations with fluorescent multiplex ligation dependent genome amplification, followed by separation in a capillary sequencer, a peak spectrum is obtained that can be automatically analyzed. 24 tumor-normal patient samples were successfully matched using this method. The potential use of the developed assay for forensic applications is discussed.
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| 18. |
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| 19. |
- Mathot, Lucy, et al.
(författare)
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Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer
- 2017
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:7, s. 1730-1740
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.
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| 20. |
- McGinn, Steven, et al.
(författare)
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New Technologies for DNA analysis-A review of the READNA Project.
- 2016
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Ingår i: New Biotechnology. - : Elsevier BV. - 1876-4347 .- 1871-6784.
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Forskningsöversikt (refereegranskat)abstract
- The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received funding from the European Commission for 4 1/2 years. The objectives of the project revolved around technological developments in nucleic acid analysis. The project partners have discovered, created and developed a huge body of insights into nucleic acid analysis, ranging from improvements and implementation of current technologies to the most promising sequencing technologies that constitute a 3(rd) and 4(th) generation of sequencing methods with nanopores and in situ sequencing, respectively.
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| 21. |
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| 22. |
- Moens, Lotte N., et al.
(författare)
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Diagnostics of Primary Immunodeficiency Diseases : A Sequencing Capture Approach
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:12, s. e114901-
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Tidskriftsartikel (refereegranskat)abstract
- Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of next generation'' sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons.
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| 23. |
- Moens, Lotte N. J., et al.
(författare)
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HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples
- 2015
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Ingår i: Journal of Molecular Diagnostics. - : Elsevier BV. - 1525-1578 .- 1943-7811. ; 17:6, s. 729-739
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomotecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment Length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and Lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings.
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| 24. |
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| 25. |
- Sassi, Atfa, et al.
(författare)
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Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels
- 2014
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 133:5, s. 1410-U681
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. Objective: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. Methods: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. Results: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p. Glu340del and p. Leu83Ser). A third homozygous mutation (p. Asp502Tyr) and the p. Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. Conclusion: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.
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