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1. Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains

Author

Kuehn, Hye Sun, Sakovich, Inga S., Niemela, Julie E., Silva, Agustin A. Gil, Stoddard, Jennifer L., Polyakova, Ekaterina A., Sole, Ana Esteve, Aleshkevich, Svetlana N., Uglova, Tatjana A., Belevtsev, Mikhail V., Vertelko, Vladislav R., Shman, Tatsiana V., Kupchinskaya, Aleksandra N., Walter, Jolan E., Fleisher, Thomas A., Notarangelo, Luigi D., Peng, Xiao P., Delmonte, Ottavia M., Sharapova, Svetlana O., and Rosenzweig, Sergio D.

Subjects
United States. National Institutes of Health, Thermo Fisher Scientific Inc., Becton, Dickinson and Co., Scientific equipment and supplies industry, DNA-ligand interactions, Omalizumab, Medical test kit industry, Autoimmunity, Allergic reaction, B cells, Medical equipment and supplies industry, Allergy, DNA binding proteins, Health care industry
Abstract

AIOLOS, also known as IKZF3, is a transcription factor that is highly expressed in the lymphoid lineage and is critical for lymphocyte differentiation and development. Here, we report on 9 individuals from 3 unrelated families carrying AIOLOS variants Q402* or E82K, which led to AIOLOS haploinsufficiency through different mechanisms of action. Nonsense mutant Q402* displayed abnormal DNA binding, pericentromeric targeting, posttranscriptional modification, and transcriptome regulation. Structurally, the mutant lacked the AIOLOS zinc finger (ZF) 5-6 dimerization domain, but was still able to homodimerize with WT AIOLOS and negatively regulate DNA binding through ZF1, a previously unrecognized function for this domain. Missense mutant E82K showed overall normal AIOLOS functions; however, by affecting a redefined AIOLOS protein stability domain, it also led to haploinsufficiency. Patients with AIOLOS haploinsufficiency showed hypogammaglobulinemia, recurrent infections, autoimmunity, and allergy, but with incomplete clinical penetrance. Altogether, these data redefine the AIOLOS structure-function relationship and expand the spectrum of AIOLOS- associated diseases., Introduction The IKAROS family members consist of 5 zinc-finger (ZF) transcription factors encoded by IKZF1 to IKZF5. IKAROS (IKZF1), HELIOS (IKZF2), and AIOLOS (IKZF3) are highly expressed in the lymphoid [...]

Published
2024
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2. Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis

Author

Bosticardo, Marita, Yamazaki, Yasuhiro, Cowan, Jennifer, Giardino, Giuliana, Corsino, Cristina, Scalia, Giulia, Prencipe, Rosaria, Ruffner, Melanie, Hill, David A, Sakovich, Inga, Yemialyanava, Irma, Tam, Jonathan S, Padem, Nurcicek, Elder, Melissa E, Sleasman, John W, Perez, Elena, Niebur, Hana, Seroogy, Christine M, Sharapova, Svetlana, Gebbia, Jennifer, Kleiner, Gary Ira, Peake, Jane, Abbott, Jordan K, Gelfand, Erwin W, Crestani, Elena, Biggs, Catherine, Butte, Manish J, Hartog, Nicholas, Hayward, Anthony, Chen, Karin, Heimall, Jennifer, Seeborg, Filiz, Bartnikas, Lisa M, Cooper, Megan A, Pignata, Claudio, Bhandoola, Avinash, and Notarangelo, Luigi D

Subjects
Biomedical and Clinical Sciences, Immunology, Rare Diseases, Biotechnology, Genetics, Prevention, Vaccine Related, Biodefense, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Animals, Child, Preschool, Female, Forkhead Transcription Factors, Heterozygote, Humans, Infant, Infant, Newborn, Lymphopenia, Male, Mice, Mice, SCID, Middle Aged, T-Lymphocytes, Thymus Gland, Young Adult, FOXN1, SCID, T cell receptor excision circles, T lymphocytes, newborn screening, thymopoiesis, thymus, Biological Sciences, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

Published
2019

4. A novel transmembrane CXCR4variant that expands the WHIM genotype-phenotype paradigm

Author

Zmajkovicova, Katarina, Pawar, Sumit, Sharapova, Svetlana O., Geier, Christoph B., Wiest, Ivana, Nguyen, Chi, Monticelli, Halenya, Maier-Munsa, Sabine, Chen, Kelly, Sleasman, John W., Aleshkevich, Svetlana, Polyakova, Ekaterina, Sakovich, Inga, Warnatz, Klaus, Grimbacher, Bodo, Proietti, Michele, Sondheimer, Neal, Ujhazi, Boglarka, Gordon, Sumai, Ellison, Maryssa, Yilmaz, Melis, Walter, Jolan E., Badarau, Adriana, Taveras, Arthur G., Neff, Jadee L., Bledsoe, Jacob R., and Tarrant, Teresa K.

Published
2024
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5. Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains

Author

Kuehn, Hye Sun, primary, Sakovich, Inga S., additional, Niemela, Julie E., additional, Gil Silva, Agustin A., additional, Stoddard, Jennifer L., additional, Polyakova, Ekaterina A., additional, Esteve-Sole, Ana, additional, Aleshkevich, Svetlana N., additional, Uglova, Tatjana A., additional, Belevtsev, Mikhail V., additional, Vertelko, Vladislav R., additional, Shman, Tatsiana V., additional, Kupchinskaya, Aleksandra N., additional, Walter, Jolan E., additional, Fleisher, Thomas A., additional, Notarangelo, Luigi D., additional, Peng, Xiao P., additional, Delmonte, Ottavia Maria, additional, Sharapova, Svetlana O., additional, and Rosenzweig, Sergio D., additional

Published
2023
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6. A novel transmembrane CXCR4 variant that expands the WHIM genotype-phenotype paradigm

Author

Zmajkovicova, Katarina, Pawar, Sumit, Sharapova, Svetlana O., Geier, Christoph B., Wiest, Ivana, Nguyen, Chi, Monticelli, Halenya, Maier-Munsa, Sabine, Chen, Kelly, Sleasman, John W., Aleshkevich, Svetlana, Polyakova, Ekaterina, Sakovich, Inga, Warnatz, Klaus, Grimbacher, Bodo, Proietti, Michele, Sondheimer, Neal, Ujhazi, Boglarka, Gordon, Sumai, Ellison, Maryssa, Yilmaz, Melis, Walter, Jolan E., Badarau, Adriana, Taveras, Arthur G., Neff, Jadee L., Bledsoe, Jacob R., and Tarrant, Teresa K.

Published
2024
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7. Variable CD18 expression in a 22‐year‐old female with leukocyte adhesion deficiency I: Clinical case and literature review

Author

Bondarenko, Anastasiia V., primary, Boyarchuk, Oksana R., additional, Sakovich, Inga S., additional, Polyakova, Ekaterina A., additional, Migas, Alexander A., additional, Kupchinskaya, Aleksandra N., additional, Opalinska, Aleksandra, additional, Reich, Adam, additional, Volianska, Liubov, additional, Hilfanova, Anna M., additional, Lapiy, Fedir I., additional, Chernyshova, Liudmyla I., additional, Volokha, Alla P., additional, Zabara, Dariia V., additional, Belevtsev, Mikhail V., additional, Shman, Tatsiana V., additional, Kukharenko, Lyudmila V., additional, Goltsev, Mikhail V., additional, Dubouskaya, Tatsiana G., additional, Hancharou, Andrei Y., additional, Ji, Weizhen, additional, Lakhani, Saquib, additional, Lucas, Carrie L., additional, Aleinikova, Olga V., additional, and Sharapova, Svetlana O., additional

Published
2023
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8. Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains.

Author

Hye Sun Kuehn, Sakovich, Inga S., Niemela, Julie E., Gil Silva, Agustin A., Stoddard, Jennifer L., Polyakova, Ekaterina A., Sole, Ana Esteve, Aleshkevich, Svetlana N., Uglova, Tatjana A., Belevtsev, Mikhail V., Vertelko, Vladislav R., Shman, Tatsiana V., Kupchinskaya, Aleksandra N., Walter, Jolan E., Fleisher, Thomas A., Notarangelo, Luigi D., Peng, Xiao P., Delmonte, Ottavia M., Sharapova, Svetlana O., and Rosenzweig, Sergio D.

Subjects
*IMMUNODEFICIENCY, *PROTEIN stability, *ZINC-finger proteins, *PROTEIN domains, *DISEASE relapse
Abstract

AIOLOS, also known as IKZF3, is a transcription factor that is highly expressed in the lymphoid lineage and is critical for lymphocyte differentiation and development. Here, we report on 9 individuals from 3 unrelated families carrying AIOLOS variants Q402* or E82K, which led to AIOLOS haploinsufficiency through different mechanisms of action. Nonsense mutant Q402* displayed abnormal DNA binding, pericentromeric targeting, posttranscriptional modification, and transcriptome regulation. Structurally, the mutant lacked the AIOLOS zinc finger (ZF) 5-6 dimerization domain, but was still able to homodimerize with WT AIOLOS and negatively regulate DNA binding through ZF1, a previously unrecognized function for this domain. Missense mutant E82K showed overall normal AIOLOS functions; however, by affecting a redefined AIOLOS protein stability domain, it also led to haploinsufficiency. Patients with AIOLOS haploinsufficiency showed hypogammaglobulinemia, recurrent infections, autoimmunity, and allergy, but with incomplete clinical penetrance. Altogether, these data redefine the AIOLOS structure-function relationship and expand the spectrum of AIOLOS-associated diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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9. The Morphologic Spectrum of Myelokathexis in WHIM Syndrome and Germline CXCR4 Variants: New Insights into Cellular Changes in the Bone Marrow and Peripheral Blood

Author

Bledsoe, Jacob R., primary, Delecourt-Billet, Marine, additional, Kelley, Merideth L., additional, Fenneteau, Odile, additional, Geier, Christoph B., additional, Neff, Jadee, additional, Yilmaz, Melis, additional, Sakovich, Inga, additional, Sharapova, Svetlana, additional, Neri, Lori, additional, Moschese, Viviana, additional, Walter, Jolan E., additional, Cavieres, Mirta, additional, Akahane, Daigo, additional, Mousallem, Talal, additional, Tarrant, Teresa, additional, Li, Julie, additional, Bolyard, Audrey Anna, additional, Mauriello, Alessandro, additional, Sockel, Katja, additional, Newburger, Peter E., additional, Donadieu, Jean, additional, and Dale, David C., additional

Published
2022
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10. Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5

Author

Sharapova, Svetlana O., primary, Pashchenko, Olga E., additional, Bondarenko, Anastasiia V., additional, Vakhlyarskaya, Svetlana S., additional, Prokofjeva, Tatjana, additional, Fedorova, Alina S., additional, Savchak, Ihor, additional, Mareika, Yuliya, additional, Valiev, Timur T., additional, Popa, Alexander, additional, Tuzankina, Irina A., additional, Vlasova, Elena V., additional, Sakovich, Inga S., additional, Polyakova, Ekaterina A., additional, Rumiantseva, Natalia V., additional, Naumchik, Irina V., additional, Kulyova, Svetlana A., additional, Aleshkevich, Svetlana N., additional, Golovataya, Elena I., additional, Minakovskaya, Nina V., additional, Belevtsev, Mikhail V., additional, Latysheva, Elena A., additional, Latysheva, Tatiana V., additional, Beznoshchenko, Alexander G., additional, Akopyan, Hayane, additional, Makukh, Halyna, additional, Kozlova, Olena, additional, Varabyou, Dzmitry S., additional, Ballow, Mark, additional, Ong, Mei-Sing, additional, Walter, Jolan E., additional, Kondratenko, Irina V., additional, Kostyuchenko, Larysa V., additional, and Aleinikova, Olga V., additional

Published
2021
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11. Novel LRBA Mutation and Possible Germinal Mosaicism in a Slavic Family

Author

Sharapova, Svetlana O., Haapaniemi, Emma, Sakovich, Inga S., Rojas, Jessica, Gamez-Diaz, Laura, Mareika, Yuliya E., Guryanova, Irina E., Migas, Alexandr A., Mikhaleuskaya, Taisiya M., Grimbacher, Bodo, Aleinikova, Olga V., Research Programs Unit, Genome-Scale Biology (GSB) Research Program, and University of Helsinki

Subjects
Slavic family, IMMUNODEFICIENCY, germline mosaicism, IMMUNE DYSREGULATION, AUTOIMMUNITY, education, LRBA homozygous mutation, STEM-CELL TRANSPLANTATION, INHERITANCE, PATIENT, DISEASE, DEFICIENCY, GENE MUTATION, GONADAL MOSAICISM, multiple autoimmunity, 3111 Biomedicine
Published
2018

12. The Morphologic Spectrum of Myelokathexis in WHIM Syndrome and Germline CXCR4Variants: New Insights into Cellular Changes in the Bone Marrow and Peripheral Blood

Author

Bledsoe, Jacob R., Delecourt-Billet, Marine, Kelley, Merideth L., Fenneteau, Odile, Geier, Christoph B., Neff, Jadee, Yilmaz, Melis, Sakovich, Inga, Sharapova, Svetlana, Neri, Lori, Moschese, Viviana, Walter, Jolan E., Cavieres, Mirta, Akahane, Daigo, Mousallem, Talal, Tarrant, Teresa, Li, Julie, Bolyard, Audrey Anna, Mauriello, Alessandro, Sockel, Katja, Newburger, Peter E., Donadieu, Jean, and Dale, David C.

Published
2022
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13. Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis

Author

Svetlana O. Sharapova, Christine M. Seroogy, Nurcicek Padem, Claudio Pignata, Jane Peake, Manish J. Butte, Marita Bosticardo, Anthony R. Hayward, Megan A. Cooper, Elena E. Perez, David A. Hill, Catherine M. Biggs, Nicholas L. Hartog, Jennifer Gebbia, Erwin W. Gelfand, Luigi D. Notarangelo, John W. Sleasman, Melissa E. Elder, Avinash Bhandoola, Cristina Corsino, Rosaria Prencipe, Jonathan S. Tam, Gary Kleiner, Jennifer Heimall, Lisa M. Bartnikas, Hana B. Niebur, Jennifer E. Cowan, Karin Chen, Jordan K. Abbott, Yasuhiro Yamazaki, Filiz O. Seeborg, Giuliana Giardino, Giulia Scalia, Irma Yemialyanava, Melanie A. Ruffner, Elena Crestani, Inga S. Sakovich, Bosticardo, Marita, Yamazaki, Yasuhiro, Cowan, Jennifer, Giardino, Giuliana, Corsino, Cristina, Scalia, Giulia, Prencipe, Rosaria, Ruffner, Melanie, Hill, DAVID STANLEY, Sakovich, Inga, Yemialyanava, Irma, Tam, Jonathan S, Padem, Nurcicek, Elder, Melissa E, Sleasman, John W, Perez, Elena, Niebur, Hana, Seroogy, Christine M, Sharapova, Svetlana, Gebbia, Jennifer, Kleiner, Gary Ira, Peake, Jane, Abbott, Jordan K, Gelfand, Erwin W, Crestani, Elena, Biggs, Catherine, Butte, Manish J, Hartog, Nichola, Hayward, Anthony, Chen, Karin, Heimall, Jennifer, Seeborg, Filiz, Bartnikas, Lisa M, Cooper, Megan A, Pignata, Claudio, Bhandoola, Avinash, and Notarangelo, Luigi D

Subjects
Male, 0301 basic medicine, FOXN1, T-Lymphocytes, Mice, SCID, Medical and Health Sciences, Mice, 0302 clinical medicine, thymus, T lymphocyte, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Genetics & Heredity, integumentary system, T-cell receptor excision circles, Forkhead Transcription Factors, Middle Aged, Biological Sciences, Phenotype, T cell receptor excision circle, Child, Preschool, T cell receptor excision circles, thymopoiesis, Female, Haploinsufficiency, Biotechnology, Adult, Heterozygote, T lymphocytes, Thymus Gland, thymopoiesi, Biology, SCID, Gene dosage, Article, Vaccine Related, Young Adult, 03 medical and health sciences, Rare Diseases, Lymphopenia, Biodefense, Genetics, medicine, Animals, Humans, Preschool, Aged, Severe combined immunodeficiency, newborn screening, Prevention, Infant, Newborn, Infant, Newborn, medicine.disease, 030104 developmental biology, Immunology, CCL25, CD8, 030215 immunology
Abstract

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of Tcell receptor excision circles (TRECs) and Tcell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent Tcell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cellcounts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of Tcell lymphopenia at birth.

Published
2019

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