@article {905, title = {Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.}, journal = {J Exp Med}, volume = {217}, year = {2020}, month = {2020 06 01}, abstract = {

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients{\textquoteright} heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

}, keywords = {Adolescent, Alleles, C-Reactive Protein, Cell Membrane, Cells, Cultured, Child, Cytokine Receptor gp130, Cytokines, Female, Fibroblasts, Genes, Dominant, Genetics, Population, HEK293 Cells, Humans, Job Syndrome, Kinetics, Loss of Function Mutation, Male, Middle Aged, Models, Biological, Mutation, Pedigree, Phenotype, Th2 Cells, Up-Regulation, Young Adult}, issn = {1540-9538}, doi = {10.1084/jem.20191804}, author = {B{\'e}ziat, Vivien and Tavernier, Simon J and Chen, Yin-Huai and Ma, Cindy S and Materna, Marie and Laurence, Arian and Staal, Jens and Aschenbrenner, Dominik and Roels, Lisa and Worley, Lisa and Claes, Kathleen and Gartner, Lisa and Kohn, Lisa A and De Bruyne, Marieke and Schmitz-Abe, Klaus and Charbonnier, Louis-Marie and Keles, Sevgi and Nammour, Justine and Vladikine, Natasha and Maglorius Renkilaraj, Majistor Raj Luxman and Seeleuthner, Yoann and Migaud, M{\'e}lanie and Rosain, J{\'e}r{\'e}mie and Jeljeli, Mohamed and Boisson, Bertrand and Van Braeckel, Eva and Rosenfeld, Jill A and Dai, Hongzheng and Burrage, Lindsay C and Murdock, David R and Lambrecht, Bart N and Avettand-Fenoel, V{\'e}ronique and Vogel, Tiphanie P and Esther, Charles R and Haskologlu, Sule and Dogu, Figen and Ciznar, Peter and Boutboul, David and Ouach{\'e}e-Chardin, Marie and Amourette, Jean and Lebras, Marie-No{\"e}lle and Gauvain, Cl{\'e}ment and Tcherakian, Colas and Ikinciogullari, Aydan and Beyaert, Rudi and Abel, Laurent and Milner, Joshua D and Grimbacher, Bodo and Couderc, Louis-Jean and Butte, Manish J and Freeman, Alexandra F and Catherinot, Emilie and Fieschi, Claire and Chatila, Talal A and Tangye, Stuart G and Uhlig, Holm H and Haerynck, Filomeen and Casanova, Jean-Laurent and Puel, Anne} } @article {619, title = {Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.}, journal = {Blood}, volume = {132}, year = {2018}, month = {2018 Jul 05}, pages = {89-100}, abstract = {

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19\%) and correlated with presentation at younger than 1 year of age ( < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58\%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45\%, and increased mortality correlated with HLH triggered by infection or malignancy ( < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

}, issn = {1528-0020}, doi = {10.1182/blood-2017-11-814244}, author = {Chinn, Ivan K and Eckstein, Olive S and Peckham-Gregory, Erin C and Goldberg, Baruch R and Forbes, Lisa R and Nicholas, Sarah K and Mace, Emily M and Vogel, Tiphanie P and Abhyankar, Harshal A and Diaz, Maria I and Heslop, Helen E and Krance, Robert A and Martinez, Caridad A and Nguyen, Trung C and Bashir, Dalia A and Goldman, Jordana R and Stray-Pedersen, Asbj{\o}rg and Pedroza, Luis A and Poli, M Cecilia and Aldave-Becerra, Juan C and McGhee, Sean A and Al-Herz, Waleed and Chamdin, Aghiad and Coban-Akdemir, Zeynep H and Jhangiani, Shalini N and Muzny, Donna M and Cao, Tram N and Hong, Diana N and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and McClain, Kenneth L and Allen, Carl E} } @article {473, title = {Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 06 07}, pages = {1126-1142}, abstract = {

The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that~perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in~any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune~phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.

}, keywords = {Base Sequence, Cell Line, Endoplasmic Reticulum Stress, Exons, Family, Frameshift Mutation, Genetic Predisposition to Disease, Heterozygote, Humans, Immunologic Deficiency Syndromes, Immunophenotyping, Infant, Newborn, Inflammation, Interferon Type I, Male, Molecular Chaperones, Mutant Proteins, Mutation, Nonsense Mediated mRNA Decay, Phenotype, Proteasome Endopeptidase Complex, RNA, Messenger, Syndrome, Unfolded Protein Response}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.04.010}, author = {Poli, M Cecilia and Ebstein, Fr{\'e}d{\'e}ric and Nicholas, Sarah K and de Guzman, Marietta M and Forbes, Lisa R and Chinn, Ivan K and Mace, Emily M and Vogel, Tiphanie P and Carisey, Alexandre F and Benavides, Felipe and Coban-Akdemir, Zeynep H and Gibbs, Richard A and Jhangiani, Shalini N and Muzny, Donna M and Carvalho, Claudia M B and Schady, Deborah A and Jain, Mahim and Rosenfeld, Jill A and Emrick, Lisa and Lewis, Richard A and Lee, Brendan and Zieba, Barbara A and K{\"u}ry, S{\'e}bastien and Kr{\"u}ger, Elke and Lupski, James R and Bostwick, Bret L and Orange, Jordan S} } @article {215, title = {Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.}, journal = {Blood}, volume = {125}, year = {2015}, month = {2015 Jan 22}, pages = {591-9}, abstract = {

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as $\#$NCT00001350.

}, keywords = {Adolescent, Adult, Autoimmune Diseases, Child, Child, Preschool, Female, Genetic Diseases, Inborn, Humans, Infant, Lymphoproliferative Disorders, Male, Mutation, Phosphorylation, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, T-Lymphocytes, Regulatory}, issn = {1528-0020}, doi = {10.1182/blood-2014-09-602763}, author = {Milner, Joshua D and Vogel, Tiphanie P and Forbes, Lisa and Ma, Chi A and Stray-Pedersen, Asbj{\o}rg and Niemela, Julie E and Lyons, Jonathan J and Engelhardt, Karin R and Zhang, Yu and Topcagic, Nermina and Roberson, Elisha D O and Matthews, Helen and Verbsky, James W and Dasu, Trivikram and Vargas-Hernandez, Alexander and Varghese, Nidhy and McClain, Kenneth L and Karam, Lina B and Nahmod, Karen and Makedonas, George and Mace, Emily M and Sorte, Hanne S and Perminow, G{\o}ri and Rao, V Koneti and O{\textquoteright}Connell, Michael P and Price, Susan and Su, Helen C and Butrick, Morgan and McElwee, Joshua and Hughes, Jason D and Willet, Joseph and Swan, David and Xu, Yaobo and Santibanez-Koref, Mauro and Slowik, Voytek and Dinwiddie, Darrell L and Ciaccio, Christina E and Saunders, Carol J and Septer, Seth and Kingsmore, Stephen F and White, Andrew J and Cant, Andrew J and Hambleton, Sophie and Cooper, Megan A} }