Article record

常染色体隐性HOXA3缺陷导致先天性无胸腺和喉畸形。

Autosomal recessive HOXA3 deficiency causes congenital athymia and laryngeal malformation.

基础研究咽喉科IF 11.6Q1

文献信息

PMID	42805310
原文	在 PubMed 查看原文 ↗
发表日期	2026
作者	Sarah S Dinges 查看其他 39 位作者 Marita Bosticardo；Anke Hirschfelder；Francesca Pala；Johannes Kopp；Viktor Glaser；Johannes Gru Nhagen；Giuseppe Sangiorgio；Lisa Ehlers；Pawel Durek；Olga Staudacher；Mirjam Völler；Austen Worth；Uwe Kölsch；Zainab M Golwala；Nadine Unterwalder；Erwin Lankes；Karl-Ulrich Schunck；Frederik Heinrich；Kayla Amini；Stavros Loukogeorgakis；Evey Howley；Heather Kenney；Hendrik S Fischer；Sven C Weber；Oliver Blankenstein；Christian Meisel；Anke Wendt；Harald Stachelscheid；Angela Kaindl；Christoph Bu Hrer；Anita Balázs；Mir-Farzin Mashreghi；Julia K Polansky；Dimitrios L Wagner；E Graham Davies；Marcus A Mall；Alexandra Y Kreins；Luigi D Notarangelo；Horst von Bernuth
作者单位	Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Augustenburger Platz 1, 13353 Berlin, Germany; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, 20892, USA; Berlin Institute of Health at Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health at Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin; 10117 Berlin, Germany. 查看其他 27 条单位信息 Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, 20892, USA.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Audiology and Phoniatrics, Augustenburger Platz 1, 13353 Berlin, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Chronically Sick Children, Augustenburger Platz 1, 13353 Berlin, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Pediatric Head & Neck Center, Augustenburger Platz 1, 13353 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Genetics and Human Genetics, Augustenburger Platz 1, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, Human Molecular Genomics Group, Berlin, Germany.；Berlin Institute of Health at Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Center for Advanced Therapies (BeCAT), Augustenburger Platz 1, 13353 Berlin, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute for Medical Immunology, Charité - Universitätsmedizin; Berlin, 10117, Germany, Augustenburger Platz 1, 13353 Berlin, Germany.；Labor Berlin GmbH, Department of Human Genetics, Sylter Straße 2, 13353 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health at Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin; 10117 Berlin, Germany; German Rheumatology Research Centre, a Leibniz Institute (DRFZ), Charitéplatz 1, 10117 Berlin, Germany.；German Rheumatology Research Centre, a Leibniz Institute (DRFZ), Charitéplatz 1, 10117 Berlin, Germany; Zuse Visual and Data-centric Computing, Zuse Institute Berlin (ZIB), Takustraße 7, 14195 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Augustenburger Platz 1, 13353 Berlin, Germany; Labor Berlin GmbH, Department of Immunology, Sylter Straße 2, 13353 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health at Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin; 10117 Berlin, Germany.；Great Ormond Street Hospital for Children NHS Foundation Trust, Department of Paediatric Immunology and Gene Therapy, London, WC1N 3JH, UK.；Labor Berlin GmbH, Department of Immunology, Sylter Straße 2, 13353 Berlin, Germany.；Great Ormond Street Hospital for Children NHS Foundation Trust, Department of Paediatric Immunology and Gene Therapy, London, WC1N 3JH, UK; UCL Great Ormond Street Institute of Child Health, Infection Immunity and Inflammation Research & Teaching Department, London, WC1N 3JH, UK.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Endocrinology and Diabetology, Augustenburger Platz 1, 13353 Berlin, Germany.；Vivantes Klinikum im Friedrichshain, Children's Hospital, Landsberger Alle 49, 10249 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neonatology, Augustenburger Platz 1, 13353 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Cardiology, Augustenburger Platz 1, 13353 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute for Medical Immunology, Charité - Universitätsmedizin; Berlin, 10117, Germany, Augustenburger Platz 1, 13353 Berlin, Germany; Labor Berlin GmbH, Department of Immunology, Sylter Straße 2, 13353 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Augustenburger Platz 1, 13353 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Stem Cell Core, Berlin Institute of Heath, Augustenburger Platz 1, 13353 Berlin, Germany.；German Center for Child and Adolescent Health (DZKJ), partner site Berlin; 10117 Berlin, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Chronically Sick Children, Augustenburger Platz 1, 13353 Berlin, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Pediatric Head & Neck Center, Augustenburger Platz 1, 13353 Berlin, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Neurology, Augustenburger Platz 1, 13353 Berlin, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German Epilepsy Center for Children and Adolescents, Augustenburger Platz 1, 13353 Berlin, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Cell- and Neurobiology, Augustenburger Platz 1, 13353 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Augustenburger Platz 1, 13353 Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin; 10117 Berlin, Germany; German Center for Lung Research (DZL), partner site Berlin; Berlin, 10117, Germany.；Berlin Institute of Health at Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin; 10117 Berlin, Germany; German Rheumatology Research Centre, a Leibniz Institute (DRFZ), Charitéplatz 1, 10117 Berlin, Germany.；Berlin Institute of Health at Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany; German Rheumatology Research Centre, a Leibniz Institute (DRFZ), Charitéplatz 1, 10117 Berlin, Germany.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Augustenburger Platz 1, 13353 Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin; 10117 Berlin, Germany; German Center for Lung Research (DZL), partner site Berlin; Berlin, 10117, Germany; Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Cluster of Excellence ImmunoPreCept, Augustenburger Platz 1, 13353 Berlin, Germany.；Great Ormond Street Hospital for Children NHS Foundation Trust, Department of Paediatric Immunology and Gene Therapy, London, WC1N 3JH, UK; UCL Great Ormond Street Institute of Child Health, Infection Immunity and Inflammation Research & Teaching Department, London, WC1N 3JH, UK. Electronic address: a.kreins@ucl.ac.uk.；Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, 20892, USA. Electronic address: luigi.notarangelo2@nih.gov.；Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health at Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health at Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin; 10117 Berlin, Germany; Labor Berlin GmbH, Department of Immunology, Sylter Straße 2, 13353 Berlin, Germany. Electronic address: horst.von-bernuth@charite.de.
期刊	The Journal of allergy and clinical immunology
SCI 分区	Q1
IF	11.6
研究类型	基础研究 · 基础／转化
所属专科	咽喉科

中文摘要

背景： 约10%的重症联合免疫缺陷（SCID）表型患者缺乏已知的遗传病因。特别是，胸腺缺陷的分子基础尚不清楚。同源盒（HOX）基因编码控制身体空间发育的保守转录因子。人类HOXA3的功能尚未明确。
目的： 我们描述首例HOXA3缺陷人类患者，并研究HOXA3在免疫系统发育中的作用。
方法： 我们进行了临床和免疫表型分析，以及基因测序。鉴定出HOXA3中的纯合无义变异，并通过RT-PCR、蛋白质印迹、转录活性评估和HOXA3的细胞内定位进行功能验证。我们报告临床管理和病程。
结果： 纯合HOXA3无义变异产生截短蛋白，具有细胞质滞留和转录活性降低。临床表型包括颅面和颈部异常、严重的喉咽畸形伴会厌发育不全导致吞咽困难和误吸、中枢性呼吸障碍和胸腺发育不全。人工胸腺类器官（ATO）中的T细胞成熟和胸腺移植后的恢复表明T细胞缺陷是非造血性的。
结论： 人类HOXA3在喉和胸腺发育中具有非冗余作用。HOXA3缺陷是一种新型的、危及生命的多系统疾病。它是首个导致先天性无胸腺的人类同源盒基因疾病。这些发现扩展了SCID表型患者的诊断基因面板，并表明会厌发育不全是先天性无胸腺的一种新的特异性共病。
关键信息： 同源盒A3（HOXA3）缺陷是先天性无胸腺的一种新病因，以颅面和颈部异常以及危及生命的喉畸形为特征。与小鼠Hoxa3不同，人类HOXA3可能对甲状旁腺和甲状腺发育是冗余的。同源域缺失导致HOXA3蛋白的细胞质滞留，导致转录活性降低。
概要： 我们将HOXA3缺陷描述为先天性无胸腺的第8种遗传学定义病因，为未来患者促进挽救生命的胸腺移植。危及生命的喉畸形为先天性无胸腺提供了临床诊断线索。

英文摘要

BACKGROUND: Approximately 10% of patients with Severe Combined Immunodeficiency (SCID) phenotype lack a known genetic cause. In particular, the molecular basis of thymic defects is poorly understood. Homeobox (HOX) genes encode conserved transcription factors that control spatial body development. The function of human HOXA3 is undefined.
OBJECTIVE: We characterize the first human with HOXA3 deficiency and investigate the role of HOXA3 in immune system development.
METHODS: We performed clinical and immunological phenotyping, as well as genetic sequencing. A homozygous nonsense variant in HOXA3 was identified, and functionally validated including RT-PCR, western blot, assessment of transcriptional activity and intracellular localization of HOXA3. We report clinical management and course.
RESULTS: The homozygous HOXA3 nonsense variant generates a truncated protein with cytoplasmic retention and reduced transcriptional activity. The clinical phenotype includes craniofacial and cervical anomalies, severe laryngopharyngeal malformation with epiglottic hypoplasia causing dysphagia and aspiration, central breathing disorder, and thymus aplasia. T-cell maturation in artificial thymic organoids (ATO) and recovery after thymus transplantation establish the T-cell defect as non-hematopoietic.
CONCLUSION: Human HOXA3 has non-redundant roles for the development of larynx and thymus. HOXA3 deficiency is a novel, life-threatening multisystem disorder. It is the first human Homeobox-gene disease causing congenital athymia. These findings expand the diagnostic gene panel for patients with a SCID phenotype and indicate epiglottic hypoplasia as a new specific co-morbidity of congenital athymia.
KEY MESSAGES: Homeobox A3 (HOXA3) deficiency is a novel cause of congenital athymia, characterized by craniofacial and cervical anomalies, and life-threatening laryngeal malformation. Human HOXA3, unlike murine Hoxa3, may be redundant for parathyroid and thyroid gland development. The loss of the homeodomain causes cytoplasmic retention of the HOXA3 protein, leading to reduced transcriptional activity.
CAPSULE SUMMARY: We describe HOXA3 deficiency as the 8th genetically defined cause of congenital athymia, facilitating life-saving thymus transplantation for future patients. Life-threatening laryngeal malformations provide a clinical diagnostic clue for congenital athymia.