PAX1 is essential for development and function of the human thymus

被引：61

作者：

Yamazaki, Yasuhiro ^{[1
]}

Urrutia, Raul ^{[2
]}

Franco, Luis M. ^{[3
]}

Giliani, Silvia ^{[4
,5
]}

Zhang, Kejian ^{[6
,7
]}

Alazami, Anas M. ^{[8
,9
]}

Dobbs, A. Kerry ^{[1
]}

Masneri, Stefania ^{[4
,5
]}

Joshi, Avni ^{[10
]}

Otaizo-Carrasquero, Francisco ^{[11
]}

Myers, Timothy G. ^{[11
]}

Ganesan, Sundar ^{[12
]}

Bondioni, Maria Pia ^{[13
]}

Ho, Mai Lan ^{[14
]}

Marks, Catherine ^{[14
]}

Alajlan, Huda ^{[8
]}

Mohammed, Reem W. ^{[15
]}

Zou, Fanggeng ^{[7
,16
]}

Valencia, C. Alexander ^{[7
,17
,18
,19
]}

Filipovich, Alexandra H. ^{[20
]}

Facchetti, Fabio ^{[4
]}

Boisson, Bertrand ^{[21
,22
,23
]}

Azzari, Chiara ^{[24
,25
]}

Al-Saud, Bander K. ^{[15
,26
]}

Al-Mousa, Hamoud ^{[15
,26
]}

Casanova, Jean Laurent ^{[21
,22
,23
,27
,28
]}

Abraham, Roshini S. ^{[29
,30
]}

Notarangelo, Luigi D. ^{[1
]}

机构：

[1] NIAID, Lab Clin Immunol & Microbiol, NIH, Bethesda, MD 20892 USA

[2] Med Coll Wisconsin, Human & Mol Genet Ctr, Milwaukee, MI USA

[3] NIAMS, Syst Autoimmun Branch, NIH, Bethesda, MD 20892 USA

[4] Univ Brescia, Dept Mol & Translat Med, Brescia, Italy

[5] Spedali Civili Hosp, A Nocivelli Inst Mol Med, Cytogenet & Med Genet Unit, Brescia, Italy

[6] Coyote Biosci USA Inc, San Jose, CA 95138 USA

[7] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Coll Med, Cincinnati, OH 45229 USA

[8] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia

[9] King Abdulaziz City Sci & Technol, Saudi Human Genome Program, Riyadh, Saudi Arabia

[10] Mayo Clin, Div Pediat Allergy & Immunol, Childrens Ctr, Rochester, MN USA

[11] NIAID, Genom Technol Sect, NIH, Bethesda, MD 20892 USA

[12] NIAID, Res Technol Branch, DIR, NIH, Bethesda, MD 20892 USA

[13] Univ Brescia, Dept Med & Surg Specialties Radiol Sci & Publ Hlt, Brescia, Italy

[14] Mayo Clin, Dept Radiol, Rochester, MN USA

[15] Alfaisal Univ, Riyadh, Saudi Arabia

[16] GeneDx Inc, Gaithersburg, MD 20877 USA

[17] PerkinElmer Genom, Pittsburgh, PA 15275 USA

[18] Sichuan Univ, West China Hosp, Dept Geriatr, Chengdu, Peoples R China

[19] Aperiomics Inc, Sterling, VA 20166 USA

[20] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Canc & Blood Inst, Coll Med, Cincinnati, OH 45229 USA

[21] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA

[22] Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, INSERM, Paris, France

[23] Paris Descartes Univ, Imagine Inst, Paris, France

[24] Univ Florence, Dept Hlth Sci, Pediat Immunol, Florence, Italy

[25] Meyer Childrens Hosp, Florence, Italy

[26] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Allergy & Immunol Sect, Riyadh 11211, Saudi Arabia

[27] Necker Hosp Sick Children, Pediat Hematol Immunol Unit, Paris, France

[28] Howard Hughes Med Inst, New York, NY 10065 USA

[29] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[30] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43205 USA

来源：

SCIENCE IMMUNOLOGY | 2020年 / 5卷 / 44期

基金：

美国国家卫生研究院;

关键词：

CELL DIFFERENTIATION; PHARYNGEAL POUCH; MUTATION; TRANSPLANTATION; GENERATION; EXPRESSION; MOUSE;

D O I：

10.1126/sciimmunol.aax1036

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.

引用

页数：14

共 48 条

[1] The scoliosis (sco)mouse:: a new allele of Pax1 [J].

Adham, IM ;

Gille, M ;

Gamel, AJ ;

Reis, A ;

Dressel, R ;

Steding, G ;

Brand-Saberi, B ;

Engel, W .

CYTOGENETIC AND GENOME RESEARCH, 2005, 111 (01) :16-26

[2] UNDULATED, A MUTATION AFFECTING THE DEVELOPMENT OF THE MOUSE SKELETON, HAS A POINT MUTATION IN THE PAIRED BOX OF PAX-1 [J].

BALLING, R ;

DEUTSCH, U ;

GRUSS, P .

CELL, 1988, 55 (03) :531-535

[3] A novel Foxn1eGFP/+ mouse model identifies Bmp4-induced maintenance of Foxn1 expression and thymic epithelial progenitor populations [J].

Barsanti, Marco ;

Lim, Joanna M. C. ;

Hun, Michael L. ;

Lister, Natalie ;

Wong, Kahlia ;

Hammett, Maree V. ;

Lepletier, Ailin ;

Boyd, Richard L. ;

Giudice, Antonietta ;

Chidgey, Ann P. .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2017, 47 (02) :291-304

[4] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[5] Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis [J].

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 ;

Notarangelo, Luigi D. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2019, 105 (03) :549-561

[6] ΔNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2 [J].

Candi, Eleonora ;

Rufini, Alessandro ;

Terrinoni, Alessandro ;

Giamboi-Miraglia, Alessandro ;

Lena, Anna Maria ;

Mantovani, Roberto ;

Knight, Richard ;

Melino, Gerry .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (29) :11999-12004

[7] Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency [J].

Ciancanelli, Michael J. ;

Huang, Sarah X. L. ;

Luthra, Priya ;

Garner, Hannah ;

Itan, Yuval ;

Volpi, Stefano ;

Lafaille, Fabien G. ;

Trouillet, Celine ;

Schmolke, Mirco ;

Albrecht, Randy A. ;

Israelsson, Elisabeth ;

Lim, Hye Kyung ;

Casadio, Melina ;

Hermesh, Tamar ;

Lorenzo, Lazaro ;

Leung, Lawrence W. ;

Pedergnana, Vincent ;

Boisson, Bertrand ;

Okada, Satoshi ;

Picard, Capucine ;

Ringuier, Benedicte ;

Troussier, Francoise ;

Chaussabel, Damien ;

Abel, Laurent ;

Pellier, Isabelle ;

Notarangelo, Luigi D. ;

Garcia-Sastre, Adolfo ;

Basler, Christopher F. ;

Geissmann, Frederic ;

Zhang, Shen-Ying ;

Snoeck, Hans-Willem ;

Casanova, Jean-Laurent .

SCIENCE, 2015, 348 (6233) :448-453

[8] Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia [J].

Das, P ;

Stockton, DW ;

Bauer, C ;

Shaffer, LG ;

D'Souza, RN ;

Wright, JT ;

Patel, PI .

HUMAN GENETICS, 2002, 110 (04) :371-376

[9] Thymus transplantation for complete DiGeorge syndrome: European experience [J].

Davies, E. Graham ;

Cheung, Melissa ;

Gilmour, Kimberly ;

Maimaris, Jesmeen ;

Curry, Joe ;

Furmanski, Anna ;

Sebire, Neil ;

Halliday, Neil ;

Mengrelis, Konstantinos ;

Adams, Stuart ;

Bernatoniene, Jolanta ;

Bremner, Ronald ;

Browning, Michael ;

Devlin, Blythe ;

Erichsen, Hans Christian ;

Gaspar, H. Bobby ;

Hutchison, Lizzie ;

Ip, Winnie ;

Ifversen, Marianne ;

Leahy, T. Ronan ;

McCarthy, Elizabeth ;

Moshous, Despina ;

Neuling, Kim ;

Pac, Malgorzata ;

Papadopol, Alina ;

Parsley, Kathryn L. ;

Poliani, Luigi ;

Ricciardelli, Ida ;

Sansom, David M. ;

Voor, Tiia ;

Worth, Austen ;

Crompton, Tessa ;

Markert, M. Louise ;

Thrasher, Adrian J. .

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2017, 140 (06) :1660-+

[10] UNDULATED PHENOTYPES SUGGEST A ROLE OF PAX-1 FOR THE DEVELOPMENT OF VERTEBRAL AND EXTRAVERTEBRAL STRUCTURES [J].

DIETRICH, S ;

GRUSS, P .

DEVELOPMENTAL BIOLOGY, 1995, 167 (02) :529-548

← 1 2 3 4 5 →