{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T08:47:52Z","timestamp":1790412472094,"version":"4.1.0"},"reference-count":20,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,1,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <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\u2212\/\u2212 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>","DOI":"10.1182\/blood.2020006441","type":"journal-article","created":{"date-parts":[[2020,9,9]],"date-time":"2020-09-09T16:18:19Z","timestamp":1599668299000},"page":"493-499","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":49,"title":["Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency"],"prefix":"10.1182","volume":"137","author":[{"given":"Francesco","family":"Saettini","sequence":"first","affiliation":[{"name":"Pediatric Hematology Department, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM), University of Milano Bicocca, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6817-0573","authenticated-orcid":false,"given":"Cecilia","family":"Poli","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX;"},{"name":"Facultad de Medicina Cl\u00ednica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-935X","authenticated-orcid":false,"given":"Jaime","family":"Vengoechea","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, GA;"},{"name":"Department of Medicine, Emory University, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Bonanomi","sequence":"additional","affiliation":[{"name":"Pediatric Hematology Department, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM), University of Milano Bicocca, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9807-7273","authenticated-orcid":false,"given":"Julio C.","family":"Orellana","sequence":"additional","affiliation":[{"name":"Division Alergia e Inmunolog\u00eda Cl\u00ednica, Hospital de Ni\u00f1os de la Sant\u00edsima Trinidad, C\u00f3rdoba, Argentina;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Fazio","sequence":"additional","affiliation":[{"name":"Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4833-3483","authenticated-orcid":false,"suffix":"III","given":"Fred H.","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Section of Cardiology, Department of Medicine, and"},{"name":"Section of Cardiology, Department of Pediatrics, Emory University, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6373-5376","authenticated-orcid":false,"given":"Loreani P.","family":"Noguera","sequence":"additional","affiliation":[{"name":"Facultad de Medicina Cl\u00ednica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2626-5037","authenticated-orcid":false,"given":"Claire","family":"Booth","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Immunology Section, UCL Institute of Child Health, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Jarur-Chamy","sequence":"additional","affiliation":[{"name":"Facultad de Medicina Cl\u00ednica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa","family":"Shams","sequence":"additional","affiliation":[{"name":"Department of Medicine, Emory University, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory, Universit\u00e0 Settore Scientifico-Disciplinare Laboratorio di Genetica Medica (USSD LGM), Papa Giovanni XXIII Hospital, Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7555-7706","authenticated-orcid":false,"given":"Maja","family":"Vukic","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Gasperini","sequence":"additional","affiliation":[{"name":"Metabolic Rare Disease Unit, Pediatric Department, Fondazione MBBM, University of Milano Bicocca, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Quadri","sequence":"additional","affiliation":[{"name":"Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7538-4553","authenticated-orcid":false,"given":"Amairelys","family":"Barroeta Seijas","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Immunology Section, UCL Institute of Child Health, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Rivers","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Immunology Section, UCL Institute of Child Health, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Mauri","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Milano Bicocca\u2013San Gerardo Hospital, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7375-5410","authenticated-orcid":false,"given":"Raffaele","family":"Badolato","sequence":"additional","affiliation":[{"name":"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;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Cazzaniga","sequence":"additional","affiliation":[{"name":"Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;"},{"name":"Department of Medicine and Surgery, University of Milano Bicocca\u2013San Gerardo Hospital, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7401-7097","authenticated-orcid":false,"given":"Cristina","family":"Bugarin","sequence":"additional","affiliation":[{"name":"Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Gaipa","sequence":"additional","affiliation":[{"name":"Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilma G. M.","family":"Kroes","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Moratto","sequence":"additional","affiliation":[{"name":"Flow Cytometry Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6772-7456","authenticated-orcid":false,"given":"Monique M.","family":"van Oostaijen-ten Dam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Baas","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8103-711X","authenticated-orcid":false,"given":"Silv\u00e8re","family":"van der Maarel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4198-9620","authenticated-orcid":false,"given":"Rocco","family":"Piazza","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Milano Bicocca\u2013San Gerardo Hospital, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep H.","family":"Coban-Akdemir","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;"},{"name":"Baylor Genetics Laboratory, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Lupski","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;"},{"name":"Baylor-Hopkins Center for Mendelian Genomics, Houston, TX; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7278-5116","authenticated-orcid":false,"given":"Bo","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;"},{"name":"Baylor Genetics Laboratory, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5684-5457","authenticated-orcid":false,"given":"Ivan K.","family":"Chinn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX;"},{"name":"Section of Immunology, Allergy, and Rheumatology, Texas Children\u2019s Hospital, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Daxinger","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Biondi","sequence":"additional","affiliation":[{"name":"Pediatric Hematology Department, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM), University of Milano Bicocca, Monza, Italy;"},{"name":"Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"1","key":"2021012816242838300_B1","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s10875-019-00706-4","article-title":"Genetic approaches for definitive diagnosis of agammaglobulinemia in consanguineous families","volume":"40","author":"Ben-Ali","year":"2020","journal-title":"J Clin Immunol"},{"issue":"42","key":"2021012816242838300_B2","doi-asserted-by":"crossref","first-page":"15552","DOI":"10.1073\/pnas.0603781103","article-title":"Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling","volume":"103","author":"Baba","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"issue":"5","key":"2021012816242838300_B3","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.immuni.2012.02.019","article-title":"Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development","volume":"36","author":"Park","year":"2012","journal-title":"Immunity"},{"issue":"2","key":"2021012816242838300_B4","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1073\/pnas.1413021112","article-title":"Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy","volume":"112","author":"Reyes","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"issue":"19","key":"2021012816242838300_B5","doi-asserted-by":"crossref","first-page":"7066","DOI":"10.1073\/pnas.1406473111","article-title":"Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development","volume":"111","author":"Park","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"issue":"26","key":"2021012816242838300_B6","doi-asserted-by":"crossref","first-page":"E3706","DOI":"10.1073\/pnas.1607592113","article-title":"Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity","volume":"113","author":"Siggs","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"issue":"6","key":"2021012816242838300_B7","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1182\/blood-2012-02-410407","article-title":"The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dub\u00e9 syndrome is required for murine B-cell development","volume":"120","author":"Baba","year":"2012","journal-title":"Blood"},{"issue":"11","key":"2021012816242838300_B8","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.4049\/jimmunol.1900395","article-title":"Folliculin interacting protein 1 maintains metabolic homeostasis during B cell development by modulating AMPK, mTORC1, and TFE3","volume":"203","author":"Ram\u00edrez","year":"2019","journal-title":"J Immunol"},{"issue":"7","key":"2021012816242838300_B9","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1002\/eji.201948504","article-title":"Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome","volume":"50","author":"Niehues","year":"2020","journal-title":"Eur J Immunol"},{"issue":"1","key":"2021012816242838300_B10","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jaci.2016.05.042","article-title":"Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders [published correction appears in J Allergy Clin Immunol. 2018;141(2):832]","volume":"139","author":"Stray-Pedersen","year":"2017","journal-title":"J Allergy Clin Immunol"},{"issue":"6","key":"2021012816242838300_B11","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/gm461","article-title":"Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy","volume":"5","author":"Lupski","year":"2013","journal-title":"Genome Med"},{"issue":"5","key":"2021012816242838300_B12","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"issue":"1","key":"2021012816242838300_B13","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jaci.2019.09.009","article-title":"Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: a working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology","volume":"145","author":"Chinn","year":"2020","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"2021012816242838300_B14","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1203\/00006450-200202000-00007","article-title":"Composition of precursor B-cell compartment in bone marrow from patients with X-linked agammaglobulinemia compared with healthy children","volume":"51","author":"Noordzij","year":"2002","journal-title":"Pediatr Res"},{"issue":"4","key":"2021012816242838300_B15","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/leu.2008.265","article-title":"Aberrant GM-CSF signal transduction pathway in juvenile myelomonocytic leukemia assayed by flow cytometric intracellular STAT5 phosphorylation measurement","volume":"23","author":"Gaipa","year":"2009","journal-title":"Leukemia"},{"issue":"6","key":"2021012816242838300_B16","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1080\/14767058.2018.1506443","article-title":"Intrauterine growth restriction associated with paternal isodisomy of chromosome 5: a clinical report and literature survey","volume":"33","author":"Kunwar","year":"2020","journal-title":"J Matern Fetal Neonatal Med"},{"issue":"6","key":"2021012816242838300_B17","doi-asserted-by":"crossref","first-page":"e0197973","DOI":"10.1371\/journal.pone.0197973","article-title":"Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation","volume":"13","author":"Centini","year":"2018","journal-title":"PLoS One"},{"issue":"4","key":"2021012816242838300_B18","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/ni.2234","article-title":"The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils","volume":"13","author":"Honda","year":"2012","journal-title":"Nat Immunol"},{"issue":"4","key":"2021012816242838300_B19","doi-asserted-by":"crossref","first-page":"e171","DOI":"10.1111\/bjh.16585","article-title":"Intermittent granulocyte maturation arrest, hypocellular bone marrow, and episodic normal neutrophil count can be associated with SRP54 mutations causing Shwachman-Diamond-like syndrome","volume":"189","author":"Saettini","year":"2020","journal-title":"Br J Haematol"},{"issue":"5","key":"2021012816242838300_B20","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1182\/blood-2012-08-447367","article-title":"High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia","volume":"121","author":"Pasquet","year":"2013","journal-title":"Blood"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/137\/4\/493\/1798300\/bloodbld2020006441.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/137\/4\/493\/1798300\/bloodbld2020006441.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T18:42:50Z","timestamp":1611859370000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/137\/4\/493\/463718\/Absent-B-cells-agammaglobulinemia-and-hypertrophic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,28]]},"references-count":20,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,1,28]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2020006441","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,28]]}}}