@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 {341, title = {Biallelic mutations in IRF8 impair human NK cell maturation and function.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 01 03}, pages = {306-320}, abstract = {

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8-/-, but not Irf8+/-, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense.

}, keywords = {Alleles, Animals, CD56 Antigen, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Interferon Regulatory Factors, Killer Cells, Natural, Male, Mice, Mice, Knockout, Mutation, Virus Diseases}, issn = {1558-8238}, doi = {10.1172/JCI86276}, author = {Mace, Emily M and Bigley, Venetia and Gunesch, Justin T and Chinn, Ivan K and Angelo, Laura S and Care, Matthew A and Maisuria, Sheetal and Keller, Michael D and Togi, Sumihito and Watkin, Levi B and LaRosa, David F and Jhangiani, Shalini N and Muzny, Donna M and Stray-Pedersen, Asbj{\o}rg and Coban Akdemir, Zeynep and Smith, Jansen B and Hern{\'a}ndez-Sanabria, Mayra and Le, Duy T and Hogg, Graham D and Cao, Tram N and Freud, Aharon G and Szymanski, Eva P and Savic, Sinisa and Collin, Matthew and Cant, Andrew J and Gibbs, Richard A and Holland, Steven M and Caligiuri, Michael A and Ozato, Keiko and Paust, Silke and Doody, Gina M and Lupski, James R and Orange, Jordan S} } @article {173, title = {COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Jun}, pages = {654-60}, abstract = {

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.

}, keywords = {Amino Acid Sequence, Arthritis, Autoimmune Diseases, Child, Preschool, Coatomer Protein, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Genetic Association Studies, Genetic Predisposition to Disease, Golgi Apparatus, HEK293 Cells, Humans, Infant, Lod Score, Lung Diseases, Interstitial, Male, Molecular Sequence Data, Pedigree, Protein Transport}, issn = {1546-1718}, doi = {10.1038/ng.3279}, author = {Watkin, Levi B and Jessen, Birthe and Wiszniewski, Wojciech and Vece, Timothy J and Jan, Max and Sha, Youbao and Thamsen, Maike and Santos-Cortez, Regie L P and Lee, Kwanghyuk and Gambin, Tomasz and Forbes, Lisa R and Law, Christopher S and Stray-Pedersen, Asbj{\o}rg and Cheng, Mickie H and Mace, Emily M and Anderson, Mark S and Liu, Dongfang and Tang, Ling Fung and Nicholas, Sarah K and Nahmod, Karen and Makedonas, George and Canter, Debra L and Kwok, Pui-Yan and Hicks, John and Jones, Kirk D and Penney, Samantha and Jhangiani, Shalini N and Rosenblum, Michael D and Dell, Sharon D and Waterfield, Michael R and Papa, Feroz R and Muzny, Donna M and Zaitlen, Noah and Leal, Suzanne M and Gonzaga-Jauregui, Claudia and Boerwinkle, Eric and Eissa, N Tony and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and Shum, Anthony K} } @article {230, title = {Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy.}, journal = {J Clin Immunol}, volume = {34}, year = {2014}, month = {2014 Oct}, pages = {871-90}, abstract = {

PURPOSE: Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A (OMIM 605000) that results in T-cell lymphopenia and is classified as T(-)B(+)NK(+)severe combined immunodeficiency (SCID). Only two other CORO1A-kindred are known to date, thus the defining characteristics are not well delineated. We identified a unique CORO1A-kindred.

METHODS: We captured a 10-year analysis of the immune-clinical phenotypes in two affected siblings from disease debut of age 7 years. Target-specific genetic studies were pursued but unrevealing. Telomere lengths were also assessed. Whole exome sequencing (WES) uncovered the molecular diagnosis and Western blot validated findings.

RESULTS: We found the compound heterozygous CORO1A variants: c.248_249delCT (p.P83RfsX10) and a novel mutation c.1077delC (p.Q360RfsX44) (NM_007074.3) in two affected non-consanguineous siblings that manifested as absent CD4CD45RA(+) (na{\"\i}ve) T and memory B cells, low NK cells and abnormally increased double-negative (DN) ϒδ T-cells. Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers; the older female sibling also had a disfiguring granulomatous tuberculoid leprosy. Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years. The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations.

CONCLUSION: We reveal the third CORO1A-mutated kindred, with the immune phenotype of abnormal na{\"\i}ve CD4 and DN T-cells and newfound characteristics of a late/hypomorphic-like SCID of an EV-HPV mucocutaneous syndrome with also B and NK defects and shortened telomeres. Our findings contribute to the elucidation of the CORO1A-SCID-CID spectrum.

}, keywords = {Adolescent, B-Lymphocytes, CD4-Positive T-Lymphocytes, Child, DNA Mutational Analysis, Epidermodysplasia Verruciformis, Female, Genetic Predisposition to Disease, Granuloma, Heterozygote, Humans, Immunologic Memory, Killer Cells, Natural, Leprosy, Tuberculoid, Male, Microfilament Proteins, Molluscum Contagiosum, Mucous Membrane, Mutation, Papillomavirus Infections, Polymorphism, Genetic, Severe Combined Immunodeficiency, Siblings, Skin, Telomere Shortening}, issn = {1573-2592}, doi = {10.1007/s10875-014-0074-8}, author = {Stray-Pedersen, Asbjorg and Jouanguy, Emmanuelle and Crequer, Amandine and Bertuch, Alison A and Brown, Betty S and Jhangiani, Shalini N and Muzny, Donna M and Gambin, Tomasz and Sorte, Hanne and Sasa, Ghadir and Metry, Denise and Campbell, Judith and Sockrider, Marianna M and Dishop, Megan K and Scollard, David M and Gibbs, Richard A and Mace, Emily M and Orange, Jordan S and Lupski, James R and Casanova, Jean-Laurent and Noroski, Lenora M} }