Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency
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- Francesco Saettini
- Pediatric Hematology Department, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM), University of Milano Bicocca, Monza, Italy;
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- Cecilia Poli
- Department of Pediatrics, Baylor College of Medicine, Houston, TX;
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- Jaime Vengoechea
- Department of Human Genetics, Emory University, Atlanta, GA;
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- Sonia Bonanomi
- Pediatric Hematology Department, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM), University of Milano Bicocca, Monza, Italy;
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- Julio C. Orellana
- Division Alergia e Inmunología Clínica, Hospital de Niños de la Santísima Trinidad, Córdoba, Argentina;
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- Grazia Fazio
- Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;
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- Fred H. Rodriguez
- Section of Cardiology, Department of Medicine, and
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- Loreani P. Noguera
- Facultad de Medicina Clínica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile;
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- Claire Booth
- Molecular and Cellular Immunology Section, UCL Institute of Child Health, London, United Kingdom;
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- Valentina Jarur-Chamy
- Facultad de Medicina Clínica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile;
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- Marissa Shams
- Department of Medicine, Emory University, Atlanta, GA;
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- Maria Iascone
- Molecular Genetics Laboratory, Università Settore Scientifico-Disciplinare Laboratorio di Genetica Medica (USSD LGM), Papa Giovanni XXIII Hospital, Bergamo, Italy;
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- Maja Vukic
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;
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- Serena Gasperini
- Metabolic Rare Disease Unit, Pediatric Department, Fondazione MBBM, University of Milano Bicocca, Monza, Italy;
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- Manuel Quadri
- Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;
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- Amairelys Barroeta Seijas
- Molecular and Cellular Immunology Section, UCL Institute of Child Health, London, United Kingdom;
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- Elizabeth Rivers
- Molecular and Cellular Immunology Section, UCL Institute of Child Health, London, United Kingdom;
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- Mario Mauri
- Department of Medicine and Surgery, University of Milano Bicocca–San Gerardo Hospital, Monza, Italy;
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- Raffaele Badolato
- Pediatrics Clinic and Institute of Molecular Medicine A. Novicelli, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy;
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- Gianni Cazzaniga
- Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;
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- Cristina Bugarin
- Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;
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- Giuseppe Gaipa
- Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;
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- Wilma G. M. Kroes
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;
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- Daniele Moratto
- Flow Cytometry Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy;
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- Monique M. van Oostaijen-ten Dam
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands;
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- Frank Baas
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;
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- Silvère van der Maarel
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;
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- Rocco Piazza
- Department of Medicine and Surgery, University of Milano Bicocca–San Gerardo Hospital, Monza, Italy;
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- Zeynep H. Coban-Akdemir
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;
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- James R. Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;
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- Bo Yuan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;
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- Ivan K. Chinn
- Department of Pediatrics, Baylor College of Medicine, Houston, TX;
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- Lucia Daxinger
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;
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- Andrea Biondi
- Pediatric Hematology Department, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM), University of Milano Bicocca, Monza, Italy;
抄録
<jats:title>Abstract</jats:title> <jats:p>Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1−/− animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.</jats:p>
収録刊行物
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- Blood
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Blood 137 (4), 493-499, 2021-01-28
American Society of Hematology