21 results on '"Walkiewicz MA"'
Search Results
2. Case report: Deep sequencing and long-read genome sequencing refine prior genetic analyses in families with apparent gonadal mosaicism in PIK3CD -related activated PI3K delta syndrome.
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Orellana H, Yan J, Paul A, Tokita M, Ding Y, Ghosh R, Lewis KL, Davis J, Jamal L, Jodarski C, Similuk M, Saucier N, Zhu Z, Wang Y, Wu S, Ruggieri J, Su HC, Uzel G, Nahas S, Cooper M, and Walkiewicz MA
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- Humans, Female, Male, Adult, Mutation, Genetic Predisposition to Disease, Child, Gonads, Mosaicism, High-Throughput Nucleotide Sequencing, Class I Phosphatidylinositol 3-Kinases genetics, Pedigree
- Abstract
Gonadal and gonosomal mosaicism describe phenomena in which a seemingly healthy individual carries a genetic variant in a subset of their gonadal tissue or gonadal and somatic tissue(s), respectively, with risk of transmitting the variant to their offspring. In families with one or more affected offspring, occurrence of the same apparently de novo variants can be an indicator of mosaicism in either parent. Panel-based deep sequencing has the capacity to detect low-level mosaic variants with coverage exceeding the typical limit of detection provided by current, readily available sequencing techniques. In this study, we report three families with more than one affected offspring with either confirmed or apparent parental gonosomal or gonadal mosaicism for PIK3CD pathogenic variants. Data from targeted deep sequencing was suggestive of low-level maternal gonosomal mosaicism in Family 1. Through this approach we did not detect pathogenic variants in PIK3CD from parental samples in Family 2 and Family 3. We conclude that mosaicism was likely confined to the maternal gonads in Family 2. Subsequent long-read genome sequencing in Family 3 showed that the paternal chromosome harbored the pathogenic variant in PIK3CD in both affected children, consistent with paternal gonadal mosaicism. Detection of parental mosaic variants enables accurate risk assessment, informs reproductive decision-making, and provides helpful context to inform clinical management in families with PIK3CD pathogenic variants., Competing Interests: ZZ, YW, SW, JR, SN, and YD are employed by Infinity-Biologix LLC D/B/A SAMPLED. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission., (Copyright © 2024 Orellana, Yan, Paul, Tokita, Ding, Ghosh, Lewis, Davis, Jamal, Jodarski, Similuk, Saucier, Zhu, Wang, Wu, Ruggieri, NIAID Centralized Sequencing Program Working Group, Su, Uzel, Nahas, Cooper and Walkiewicz.)
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- 2024
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3. Topical Steroid Withdrawal is a Targetable Excess of Mitochondrial NAD.
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Shobnam N, Saksena S, Ratley G, Yadav M, Chaudhary PP, Sun AA, Howe KN, Gadkari M, Franco LM, Ganesan S, McCann KJ, Hsu AP, Kanakabandi K, Ricklefs S, Lack J, Yu W, Similuk M, Walkiewicz MA, Gardner DD, Barta K, Tullos K, and Myles IA
- Abstract
Background: Topical corticosteroids (TCS) are first-line therapies for numerous skin conditions. Topical Steroid Withdrawal (TSW) is a controversial diagnosis advocated by patients with prolonged TCS exposure who report severe systemic reactions upon treatment cessation. However, to date there have been no systematic clinical or mechanistic studies to distinguish TSW from other eczematous disorders., Methods: A re-analysis of a previous survey with eczematous skin disease was performed to evaluate potential TSW distinguishing symptoms. We subsequently conducted a pilot study of 16 patients fitting the proposed diagnostic criteria. We then performed: tissue metabolomics, transcriptomics, and immunostaining on skin biopsies; serum metabolomics and cytokine assessments; shotgun metagenomics on microbiome skin swabs; genome sequencing; followed by functional, mechanistic studies using human skin cell lines and mice., Results: Clinically distinct TSW symptoms included burning, flushing, and thermodysregulation. Metabolomics and transcriptomics both implicated elevated NAD+ oxidation stemming from increased expression of mitochondrial complex I and conversion of tryptophan into kynurenine metabolites. These abnormalities were induced by glucocorticoid exposure both in vitro and in a cohort of healthy controls (N=19) exposed to TCS. Targeting complex I via either metformin or the herbal compound berberine improved outcomes in both cell culture and in an open-label case series for patients with TSW., Conclusion: Taken together, our results suggest that TSW has a distinct dermatopathology. While future studies are needed to validate these results in larger cohorts, this work provides the first mechanistic evaluation into TSW pathology, and offers insights into clinical identification, pharmacogenomic candidates, and directed therapeutic strategies.
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- 2024
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4. Genetic Risk Factors for Early-Onset Merkel Cell Carcinoma.
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Mohsin N, Hunt D, Yan J, Jabbour AJ, Nghiem P, Choi J, Zhang Y, Freeman AF, Bergerson JRE, Dell'Orso S, Lachance K, Kulikauskas R, Collado L, Cao W, Lack J, Similuk M, Seifert BA, Ghosh R, Walkiewicz MA, and Brownell I
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- Humans, Middle Aged, Genetic Predisposition to Disease, Germ-Line Mutation, Risk Factors, Carcinoma, Merkel Cell epidemiology, Carcinoma, Merkel Cell genetics, Skin Neoplasms epidemiology, Skin Neoplasms genetics
- Abstract
Importance: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Of the patients who develop MCC annually, only 4% are younger than 50 years., Objective: To identify genetic risk factors for early-onset MCC via genomic sequencing., Design, Setting, and Participants: The study represents a multicenter collaboration between the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Allergy and Infectious Diseases (NIAID), and the University of Washington. Participants with early-onset and later-onset MCC were prospectively enrolled in an institutional review board-approved study at the University of Washington between January 2003 and May 2019. Unrelated controls were enrolled in the NIAID Centralized Sequencing Program (CSP) between September 2017 and September 2021. Analysis was performed from September 2021 and March 2023. Early-onset MCC was defined as disease occurrence in individuals younger than 50 years. Later-onset MCC was defined as disease occurrence at age 50 years or older. Unrelated controls were evaluated by the NIAID CSP for reasons other than familial cancer syndromes, including immunological, neurological, and psychiatric disorders., Results: This case-control analysis included 1012 participants: 37 with early-onset MCC, 45 with later-onset MCC, and 930 unrelated controls. Among 37 patients with early-onset MCC, 7 (19%) had well-described variants in genes associated with cancer predisposition. Six patients had variants associated with hereditary cancer syndromes (ATM = 2, BRCA1 = 2, BRCA2 = 1, and TP53 = 1) and 1 patient had a variant associated with immunodeficiency and lymphoma (MAGT1). Compared with 930 unrelated controls, the early-onset MCC cohort was significantly enriched for cancer-predisposing pathogenic or likely pathogenic variants in these 5 genes (odds ratio, 30.35; 95% CI, 8.89-106.30; P < .001). No germline disease variants in these genes were identified in 45 patients with later-onset MCC. Additional variants in DNA repair genes were also identified among patients with MCC., Conclusions and Relevance: Because variants in certain DNA repair and cancer predisposition genes are associated with early-onset MCC, genetic counseling and testing should be considered for patients presenting at younger than 50 years.
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- 2024
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5. TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.
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Boast B, Goel S, González-Granado LI, Niemela J, Stoddard J, Edwards ESJ, Seneviratne S, Spensberger D, Quesada-Espinosa JF, Allende LM, McDonnell J, Haseley A, Lesmana H, Walkiewicz MA, Muhammad E, Bosco JJ, Fleisher TA, Cohen S, Holland SM, van Zelm MC, Enders A, Kuehn HS, and Rosenzweig SD
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- Animals, Humans, Mice, B-Lymphocytes, Immunoglobulins genetics, T-Lymphocytes, Basic Helix-Loop-Helix Transcription Factors genetics, Haploinsufficiency, Immunologic Deficiency Syndromes genetics
- Abstract
Background: TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance., Objective: We sought to define TCF3 haploinsufficiency (HI) biology and its association with immunodeficiency., Methods: Patient clinical data and blood samples were analyzed. Flow cytometry, Western blot analysis, plasmablast differentiation, immunoglobulin secretion, and transcriptional activity studies were conducted on individuals carrying TCF3 variants. Mice with a heterozygous Tcf3 deletion were analyzed for lymphocyte development and phenotyping., Results: Individuals carrying monoallelic LOF TCF3 variants showed B-cell defects (eg, reduced total, class-switched memory, and/or plasmablasts) and reduced serum immunoglobulin levels; most but not all presented with recurrent but nonsevere infections. These TCF3 LOF variants were either not transcribed or translated, resulting in reduced wild-type TCF3 protein expression, strongly suggesting HI pathophysiology for the disease. Targeted RNA sequencing analysis of T-cell blasts from TCF3-null, dominant negative, or HI individuals clustered away from healthy donors, implying that 2 WT copies of TCF3 are needed to sustain a tightly regulated TCF3 gene-dosage effect. Murine TCF3 HI resulted in a reduction of circulating B cells but overall normal humoral immune responses., Conclusion: Monoallelic LOF TCF3 mutations cause a gene-dosage-dependent reduction in wild-type protein expression, B-cell defects, and a dysregulated transcriptome, resulting in immunodeficiency. Tcf3
+/- mice partially recapitulate the human phenotype, underscoring the differences between TCF3 in humans and mice., (Published by Elsevier Inc.)- Published
- 2023
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6. Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity.
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Beers BJ, Similuk MN, Ghosh R, Seifert BA, Jamal L, Kamen M, Setzer MR, Jodarski C, Duncan R, Hunt D, Mixer M, Cao W, Bi W, Veltri D, Karlins E, Zhang L, Li Z, Oler AJ, Jevtich K, Yu Y, Hullfish H, Bielekova B, Frischmeyer-Guerrerio P, Dang Do A, Huryn LA, Olivier KN, Su HC, Lyons JJ, Zerbe CS, Rao VK, Keller MD, Freeman AF, Holland SM, Franco LM, Walkiewicz MA, and Yan J
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- Humans, Child, Exome Sequencing, Microarray Analysis, Phenotype, Chromosomes, Genetic Testing
- Abstract
Purpose: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI., Methods: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings., Results: Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone., Conclusion: Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation., Competing Interests: WB is an employee of Baylor Genetics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer IC declared a shared affiliation, with no collaboration, with one of the authors, WB, to the handling editor at the time of the review., (Copyright © 2023 Beers, Similuk, Ghosh, Seifert, Jamal, Kamen, Setzer, Jodarski, Duncan, Hunt, Mixer, Cao, Bi, Veltri, Karlins, Zhang, Li, Oler, Jevtich, Yu, Hullfish, Bielekova, Frischmeyer-Guerrerio, Dang Do, Huryn, Olivier, Su, Lyons, Zerbe, Rao, Keller, Freeman, Holland, Franco, Walkiewicz and Yan.)
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- 2023
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7. Reappraisal of Idiopathic CD4 Lymphocytopenia at 30 Years.
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Lisco A, Ortega-Villa AM, Mystakelis H, Anderson MV, Mateja A, Laidlaw E, Manion M, Roby G, Higgins J, Kuriakose S, Walkiewicz MA, Similuk M, Leiding JW, Freeman AF, Sheikh V, and Sereti I
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- Humans, CD4-Positive T-Lymphocytes, CD4 Lymphocyte Count, COVID-19 complications, Immunologic Deficiency Syndromes complications, Lymphopenia etiology, Opportunistic Infections, Primary Immunodeficiency Diseases complications
- Abstract
Background: Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of immunodeficiency. Some 30 years after its original identification, ICL has remained a disease of obscure cause, with limited evidence with respect to its prognosis or management, despite diagnostic and therapeutic innovations., Methods: We evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. We performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against coronavirus disease 2019 (Covid-19), and mortality., Results: After the exclusion of patients with genetic and acquired causes of CD4 lymphopenia, the study population included 91 patients with ICL during 374 person-years of follow-up. The median CD4+ T-cell count among the patients was 80 cells per cubic millimeter. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was associated with a higher risk of opportunistic infection (odds ratio, 5.3; 95% confidence interval [CI], 2.8 to 10.7) and invasive cancer (odds ratio, 2.1; 95% CI, 1.1 to 4.3) and a lower risk of autoimmunity (odds ratio, 0.5; 95% CI, 0.2 to 0.9). The risk of death was similar to that in the age- and sex-adjusted general population, but the prevalence of cancer was higher., Conclusions: Among the study patients, ICL continued to be associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer. (Funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269.)., (Copyright © 2023 Massachusetts Medical Society.)
- Published
- 2023
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8. Case report: Discovery of a de novo FAM111B pathogenic variant in a patient with an APECED-like clinical phenotype.
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Ferré EMN, Yu Y, Oikonomou V, Hilfanova A, Lee CR, Rosen LB, Burbelo PD, Vazquez SE, Anderson MS, Barocha A, Heller T, Soldatos A, Holland SM, Walkiewicz MA, and Lionakis MS
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- Male, Humans, Autoantibodies, Azathioprine, Phenotype, Cell Cycle Proteins, DNA Copy Number Variations, Polyendocrinopathies, Autoimmune
- Abstract
Introduction: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and poikiloderma in association with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) are rare inherited syndromes resulting from biallelic pathogenic variants in AIRE and heterozygous pathogenic variants in FAM111B , respectively. The clinical diagnosis of APECED and POIKTMP rely on the development of two or more characteristic disease manifestations that define the corresponding syndromes. We discuss the shared and distinct clinical, radiographic, and histological features between APECED and POIKTMP presented in our patient case and describe his treatment response to azathioprine for POIKTMP-associated hepatitis, myositis, and pneumonitis., Methods: Through informed consent and enrollment onto IRB-approved protocols (NCT01386437, NCT03206099) the patient underwent a comprehensive clinical evaluation at the NIH Clinical Center alongside exome sequencing, copy number variation analysis, autoantibody surveys, peripheral blood immunophenotyping, and salivary cytokine analyses., Results: We report the presentation and evaluation of a 9-year-old boy who was referred to the NIH Clinical Center with an APECED-like clinical phenotype that included the classic APECED dyad of CMC and hypoparathyroidism. He was found to meet clinical diagnostic criteria for POIKTMP featuring poikiloderma, tendon contractures, myopathy, and pneumonitis, and exome sequencing revealed a de novo c.1292T>C heterozygous pathogenic variant in FAM111B but no deleterious single nucleotide variants or copy number variants in AIRE ., Discussion: This report expands upon the available genetic, clinical, autoantibody, immunological, and treatment response information on POIKTMP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ferré, Yu, Oikonomou, Hilfanova, Lee, Rosen, Burbelo, Vazquez, Anderson, Barocha, Heller, Soldatos, Holland, Walkiewicz and Lionakis.)
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- 2023
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9. FOXI3 haploinsufficiency contributes to low T-cell receptor excision circles and T-cell lymphopenia.
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Ghosh R, Bosticardo M, Singh S, Similuk M, Delmonte OM, Pala F, Peng C, Jodarski C, Keller MD, Chinn IK, Groves AK, Notarangelo LD, Walkiewicz MA, Chinen J, and Bundy V
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- Infant, Newborn, Child, Humans, T-Lymphocytes, Genomics, Receptors, Antigen, T-Cell genetics
- Abstract
Background: Newborn screening can identify neonatal T-cell lymphopenia through detection of a low number of copies of T-cell receptor excision circles in dried blood spots collected at birth. After a positive screening result, further diagnostic testing is required to determine whether the subject has severe combined immunodeficiency or other causes of T-cell lymphopenia. Even after thorough evaluation, approximately 15% of children with a positive result of newborn screening for T-cell receptor excision circles remain genetically undiagnosed. Identifying the underlying genetic etiology is necessary to guide subsequent clinical management and family planning., Objective: We sought to elucidate the genetic basis of patients with T-cell lymphopenia without an apparent genetic diagnosis., Methods: We used clinical genomic testing as well as functional and immunologic assays to identify and elucidate the genetic and mechanistic basis of T-cell lymphopenia., Results: We report 2 unrelated individuals with nonsevere T-cell lymphopenia and abnormal T-cell receptor excision circles who harbor heterozygous loss-of-function variants in forkhead box I3 transcription factor (FOXI3)., Conclusion: Our findings support the notion that haploinsufficiency of FOXI3 results in T-cell lymphopenia with variable expressivity and that FOXI3 may be a key modulator of thymus development., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Published
- 2022
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10. Human Dectin-1 deficiency impairs macrophage-mediated defense against phaeohyphomycosis.
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Drummond RA, Desai JV, Hsu AP, Oikonomou V, Vinh DC, Acklin JA, Abers MS, Walkiewicz MA, Anzick SL, Swamydas M, Vautier S, Natarajan M, Oler AJ, Yamanaka D, Mayer-Barber KD, Iwakura Y, Bianchi D, Driscoll B, Hauck K, Kline A, Viall NS, Zerbe CS, Ferré EM, Schmitt MM, DiMaggio T, Pittaluga S, Butman JA, Zelazny AM, Shea YR, Arias CA, Ashbaugh C, Mahmood M, Temesgen Z, Theofiles AG, Nigo M, Moudgal V, Bloch KC, Kelly SG, Whitworth MS, Rao G, Whitener CJ, Mafi N, Gea-Banacloche J, Kenyon LC, Miller WR, Boggian K, Gilbert A, Sincock M, Freeman AF, Bennett JE, Hasbun R, Mikelis CM, Kwon-Chung KJ, Belkaid Y, Brown GD, Lim JK, Kuhns DB, Holland SM, and Lionakis MS
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- Animals, Humans, Male, Mice, CARD Signaling Adaptor Proteins genetics, Lectins, C-Type genetics, Macrophages metabolism, Tumor Necrosis Factor-alpha genetics, beta-Glucans, Phaeohyphomycosis microbiology
- Abstract
Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1β-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.
- Published
- 2022
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11. Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.
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Similuk MN, Yan J, Ghosh R, Oler AJ, Franco LM, Setzer MR, Kamen M, Jodarski C, DiMaggio T, Davis J, Gore R, Jamal L, Borges A, Gentile N, Niemela J, Lowe C, Jevtich K, Yu Y, Hullfish H, Hsu AP, Hong C, Littel P, Seifert BA, Milner J, Johnston JJ, Cheng X, Li Z, Veltri D, Huang K, Kaladi K, Barnett J, Zhang L, Vlasenko N, Fan Y, Karlins E, Ganakammal SR, Gilmore R, Tran E, Yun A, Mackey J, Yazhuk S, Lack J, Kuram V, Cao W, Huse S, Frank K, Fahle G, Rosenzweig S, Su Y, Hwang S, Bi W, Bennett J, Myles IA, De Ravin SS, Fuss I, Strober W, Bielekova B, Almeida de Jesus A, Goldbach-Mansky R, Williamson P, Kumar K, Dempsy C, Frischmeyer-Guerrerio P, Fisch R, Bolan H, Metcalfe DD, Komarow H, Carter M, Druey KM, Sereti I, Dropulic L, Klion AD, Khoury P, O' Connell EM, Holland-Thomas NC, Brown T, McDermott DH, Murphy PM, Bundy V, Keller MD, Peng C, Kim H, Norman S, Delmonte OM, Kang E, Su HC, Malech H, Freeman A, Zerbe C, Uzel G, Bergerson JRE, Rao VK, Olivier KN, Lyons JJ, Lisco A, Cohen JI, Lionakis MS, Biesecker LG, Xirasagar S, Notarangelo LD, Holland SM, and Walkiewicz MA
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- Female, Genomics, Humans, Male, Phenotype, Prospective Studies, Exome genetics, Genetic Testing methods
- Abstract
Background: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges., Objectives: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health., Methods: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity., Results: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option., Conclusions: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale., (Published by Elsevier Inc.)
- Published
- 2022
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12. SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
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Delmonte OM, Bergerson JRE, Kawai T, Kuehn HS, McDermott DH, Cortese I, Zimmermann MT, Dobbs AK, Bosticardo M, Fink D, Majumdar S, Palterer B, Pala F, Dsouza NR, Pouzolles M, Taylor N, Calvo KR, Daley SR, Velez D, Agharahimi A, Myint-Hpu K, Dropulic LK, Lyons JJ, Holland SM, Freeman AF, Ghosh R, Similuk MB, Niemela JE, Stoddard J, Kuhns DB, Urrutia R, Rosenzweig SD, Walkiewicz MA, Murphy PM, and Notarangelo LD
- Subjects
- Animals, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, Child, Preschool, Chromosomes, Human, X immunology, Genetic Loci, Humans, Jurkat Cells, Killer Cells, Natural immunology, Lymphopenia genetics, Lymphopenia immunology, Male, Mice, Mice, Knockout, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta immunology, X-Linked Combined Immunodeficiency Diseases immunology, Chromosomes, Human, X genetics, Mutation, X-Linked Combined Immunodeficiency Diseases genetics
- Abstract
Sterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3), also called SH3-containing lymphocyte protein (SLY1), is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction cascades in lymphocytes. The SASH3 gene is located on the X-chromosome. Here, we identified 3 novel SASH3 deleterious variants in 4 unrelated male patients with a history of combined immunodeficiency and immune dysregulation that manifested as recurrent sinopulmonary, cutaneous, and mucosal infections and refractory autoimmune cytopenias. Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens. In vitro T-cell differentiation of CD34+ cells and molecular signatures of rearrangements at the T-cell receptor α (TRA) locus were indicative of impaired thymocyte survival. These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia. Lentivirus-mediated transfer of the SASH3 complementary DNA-corrected protein expression, in vitro proliferation, and signaling in SASH3-deficient Jurkat and patient-derived T cells. These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in mice with Sly1-/- and Sly1Δ/Δ mutations, highlighting an important role of SASH3 in human lymphocyte function and survival., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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13. Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.
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Aluri J, Bach A, Kaviany S, Chiquetto Paracatu L, Kitcharoensakkul M, Walkiewicz MA, Putnam CD, Shinawi M, Saucier N, Rizzi EM, Harmon MT, Keppel MP, Ritter M, Similuk M, Kulm E, Joyce M, de Jesus AA, Goldbach-Mansky R, Lee YS, Cella M, Kendall PL, Dinauer MC, Bednarski JJ, Bemrich-Stolz C, Canna SW, Abraham SM, Demczko MM, Powell J, Jones SM, Scurlock AM, De Ravin SS, Bleesing JJ, Connelly JA, Rao VK, Schuettpelz LG, and Cooper MA
- Subjects
- Adolescent, Adult, B-Lymphocytes pathology, Bone Marrow Failure Disorders etiology, Bone Marrow Failure Disorders metabolism, Cell Differentiation, Child, Child, Preschool, Cytokines metabolism, Female, Follow-Up Studies, Humans, Immunologic Deficiency Syndromes etiology, Immunologic Deficiency Syndromes metabolism, Infant, Inflammation etiology, Inflammation metabolism, Lymphocyte Activation, Male, Pancytopenia etiology, Pancytopenia metabolism, Pedigree, Prognosis, T-Lymphocytes immunology, Young Adult, Bone Marrow Failure Disorders pathology, Gain of Function Mutation, Immunologic Deficiency Syndromes pathology, Inflammation pathology, Mosaicism, Pancytopenia pathology, Toll-Like Receptor 8 genetics
- Abstract
Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.
- Published
- 2021
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14. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.
- Author
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Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schäffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C, Zenker M, Lee B, and Biesecker LG
- Subjects
- Adolescent, Child, Child, Preschool, Exome genetics, Female, Genetic Linkage, Genotype, Heterozygote, Humans, Infant, Male, Mutation, Noonan Syndrome pathology, Pedigree, Protein Isoforms genetics, RNA Splicing genetics, Siblings, Genetic Predisposition to Disease, Noonan Syndrome genetics, Transcription Factors genetics
- Abstract
Purpose: To characterize the molecular genetics of autosomal recessive Noonan syndrome., Methods: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction., Results: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings., Conclusion: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.
- Published
- 2018
- Full Text
- View/download PDF
15. Phenotypic expansion in DDX3X - a common cause of intellectual disability in females.
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Wang X, Posey JE, Rosenfeld JA, Bacino CA, Scaglia F, Immken L, Harris JM, Hickey SE, Mosher TM, Slavotinek A, Zhang J, Beuten J, Leduc MS, He W, Vetrini F, Walkiewicz MA, Bi W, Xiao R, Liu P, Shao Y, Gezdirici A, Gulec EY, Jiang Y, Darilek SA, Hansen AW, Khayat MM, Pehlivan D, Piard J, Muzny DM, Hanchard N, Belmont JW, Van Maldergem L, Gibbs RA, Eldomery MK, Akdemir ZC, Adesina AM, Chen S, Lee YC, Lee B, Lupski JR, Eng CM, Xia F, Yang Y, Graham BH, and Moretti P
- Abstract
De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders.
- Published
- 2018
- Full Text
- View/download PDF
16. Mutation in the ADNP gene associated with Noonan syndrome features.
- Author
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Alkhunaizi E, Walkiewicz MA, and Chitayat D
- Subjects
- Autistic Disorder physiopathology, Child, Preschool, Developmental Disabilities physiopathology, Funnel Chest genetics, Funnel Chest physiopathology, Humans, Male, Mutation, Noonan Syndrome physiopathology, Pectus Carinatum genetics, Pectus Carinatum physiopathology, Phenotype, Exome Sequencing, Autistic Disorder genetics, Developmental Disabilities genetics, Homeodomain Proteins genetics, Nerve Tissue Proteins genetics, Noonan Syndrome genetics
- Published
- 2018
- Full Text
- View/download PDF
17. Autosomal dominant distal myopathy due to a novel ACTA1 mutation.
- Author
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Liewluck T, Sorenson EJ, Walkiewicz MA, Rumilla KM, and Milone M
- Subjects
- Adult, Age of Onset, Aged, Diagnosis, Differential, Distal Myopathies diagnosis, Distal Myopathies pathology, Family, Female, Humans, Male, Muscle, Skeletal pathology, Actins genetics, Distal Myopathies genetics, Mutation genetics
- Abstract
Mutations in skeletal muscle α-actin 1-encoding gene (ACTA1) cause autosomal dominant or recessive myopathies with marked clinical and pathological heterogeneity. Patients typically develop generalized or limb-girdle pattern of weakness, but recently a family with scapuloperoneal myopathy was reported. We describe a father and 2 children with childhood-to-juvenile onset distal myopathy, carrying a novel dominant ACTA1 variant, c.757G>C (p.Gly253Arg). Father had delayed motor development and developed significant proximal weakness later in life; he was initially misdiagnosed as having spinal muscular atrophy based on electromyographic findings. His children had predominant anterior distal leg and finger extensor involvement. Nemaline rods were abundant on the daughter's biopsy, absent on the father's initial biopsy, and extremely rare on the father's subsequent biopsy a decade later. The father's second biopsy also showed myofibrillar pathology and rare fibers with actin filament aggregates. The present family expands the spectrum of actinopathy to include a distal myopathy., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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18. Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features.
- Author
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Santiago-Sim T, Burrage LC, Ebstein F, Tokita MJ, Miller M, Bi W, Braxton AA, Rosenfeld JA, Shahrour M, Lehmann A, Cogné B, Küry S, Besnard T, Isidor B, Bézieau S, Hazart I, Nagakura H, Immken LL, Littlejohn RO, Roeder E, Kara B, Hardies K, Weckhuysen S, May P, Lemke JR, Elpeleg O, Abu-Libdeh B, James KN, Silhavy JL, Issa MY, Zaki MS, Gleeson JG, Seavitt JR, Dickinson ME, Ljungberg MC, Wells S, Johnson SJ, Teboul L, Eng CM, Yang Y, Kloetzel PM, Heaney JD, and Walkiewicz MA
- Subjects
- Adolescent, Animals, Child, Child, Preschool, Disease Models, Animal, Female, Gene Deletion, Humans, Male, Mice, Pedigree, Proteasome Endopeptidase Complex genetics, Proteasome Endopeptidase Complex metabolism, Seizures genetics, Abnormalities, Multiple genetics, Endopeptidases genetics, Intellectual Disability genetics
- Abstract
Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
19. The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.
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Fountain MD, Aten E, Cho MT, Juusola J, Walkiewicz MA, Ray JW, Xia F, Yang Y, Graham BH, Bacino CA, Potocki L, van Haeringen A, Ruivenkamp CA, Mancias P, Northrup H, Kukolich MK, Weiss MM, van Ravenswaaij-Arts CM, Mathijssen IB, Levesque S, Meeks N, Rosenfeld JA, Lemke D, Hamosh A, Lewis SK, Race S, Stewart LL, Hay B, Lewis AM, Guerreiro RL, Bras JT, Martins MP, Derksen-Lubsen G, Peeters E, Stumpel C, Stegmann S, Bok LA, Santen GW, and Schaaf CP
- Subjects
- Adolescent, Adult, Autism Spectrum Disorder physiopathology, Child, Child, Preschool, Chromosomes, Human, Pair 15, Developmental Disabilities physiopathology, Female, Gene Expression, Genomic Imprinting, Humans, Infant, Infant, Newborn, Intellectual Disability physiopathology, Male, Mutation, Phenotype, Prader-Willi Syndrome physiopathology, Autism Spectrum Disorder genetics, Developmental Disabilities genetics, Intellectual Disability genetics, Prader-Willi Syndrome genetics, Proteins genetics
- Abstract
Purpose: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients' phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype., Methods: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant., Results: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints., Conclusion: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med 19 1, 45-52.
- Published
- 2017
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20. De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive.
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Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, Küry S, Besnard T, Isidor B, Latypova X, Bézieau S, Liu P, Motter CS, Melver CW, Robin NH, Infante EM, McGuire M, El-Gharbawy A, Littlejohn RO, McLean SD, Bi W, Bacino CA, Lalani SR, Scott DA, Eng CM, Yang Y, Schaaf CP, and Walkiewicz MA
- Subjects
- Adolescent, Brain abnormalities, Child, Child, Preschool, DNA-Binding Proteins chemistry, Exome genetics, Female, Humans, Male, Minor Histocompatibility Antigens chemistry, Pedigree, Young Adult, Congenital Abnormalities genetics, DNA-Binding Proteins genetics, Developmental Disabilities genetics, Failure to Thrive genetics, Intellectual Disability genetics, Minor Histocompatibility Antigens genetics, Sequence Deletion genetics
- Abstract
SON is a key component of the spliceosomal complex and a critical mediator of constitutive and alternative splicing. Additionally, SON has been shown to influence cell-cycle progression, genomic integrity, and maintenance of pluripotency in stem cell populations. The clear functional relevance of SON in coordinating essential cellular processes and its presence in diverse human tissues suggests that intact SON might be crucial for normal growth and development. However, the phenotypic effects of deleterious germline variants in SON have not been clearly defined. Herein, we describe seven unrelated individuals with de novo variants in SON and propose that deleterious variants in SON are associated with a severe multisystem disorder characterized by developmental delay, persistent feeding difficulties, and congenital malformations, including brain anomalies., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
21. Increased insulin/insulin growth factor signaling advances the onset of metamorphosis in Drosophila.
- Author
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Walkiewicz MA and Stern M
- Subjects
- Animals, Cyclic AMP-Dependent Protein Kinases antagonists & inhibitors, Enzyme Activation, Insect Hormones physiology, Phosphatidylinositol 3-Kinases metabolism, Drosophila growth & development, Insulin metabolism, Metamorphosis, Biological, Signal Transduction, Somatomedins metabolism
- Abstract
Mechanisms by which attainment of specific body sizes trigger developmental transitions to adulthood (e.g. puberty or metamorphosis) are incompletely understood. In Drosophila, metamorphosis is triggered by ecdysone synthesis from the prothoracic gland (PG), whereas growth rate is increased by insulin/insulin growth factor signalling (IIS). Transgene-induced activation of PI3K, the major effector of IIS, within the PG advances the onset of metamorphosis via precocious ecdysone synthesis, raising the possibility that IIS triggers metamorphosis via PI3K activation in the PG. Here we show that blocking the protein kinase A (PKA) pathway in the insulin producing cells (IPCs) increases IIS. This increased IIS increases larval growth rate and also advances the onset of metamorphosis, which is accompanied by precocious ecdysone synthesis and increased transcription of at least one ecdysone biosynthetic gene. Our observations suggest that IIS is regulated by PKA pathway activity in the IPCs. In addition, taken together with previous findings, our observations are consistent with the possibility that, in Drosophila, attainment of a specific body size triggers metamorphosis via the IIS-mediated activation of PI3K and hence ecdysone synthesis in the PG.
- Published
- 2009
- Full Text
- View/download PDF
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