Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.

TitleAbsent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.
Publication TypeJournal Article
Year of Publication2021
AuthorsSaettini, F, Poli, C, Vengoechea, J, Bonanomi, S, Orellana, JC, Fazio, G, Rodriguez, FH, Noguera, LP, Booth, C, Jarur-Chamy, V, Shams, M, Iascone, M, Vukic, M, Gasperini, S, Quadri, M, Seijas, ABarroeta, Rivers, E, Mauri, M, Badolato, R, Cazzaniga, G, Bugarin, C, Gaipa, G, Kroes, WGM, Moratto, D, Dam, MM van Oost, Baas, F, van der Maarel, S, Piazza, R, Coban-Akdemir, ZH, Lupski, JR, Yuan, B, Chinn, IK, Daxinger, L, Biondi, A
Date Published2021 01 28
KeywordsAdult, Agammaglobulinemia, Animals, B-Lymphocytes, Cardiomyopathy, Hypertrophic, Carrier Proteins, Child, Child, Preschool, Chromosomes, Human, Pair 5, Codon, Nonsense, Consanguinity, Crohn Disease, Developmental Disabilities, Disease Models, Animal, Disease Susceptibility, DNA Copy Number Variations, Female, Heart Defects, Congenital, Humans, Immunologic Deficiency Syndromes, Infections, Loss of Function Mutation, Lymphopenia, Male, Mice, Neutropenia, Pedigree, Uniparental Disomy, Whole Exome Sequencing

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.

Alternate JournalBlood
PubMed ID32905580
PubMed Central IDPMC7845007
Grant List 201250/Z/16/Z / WT_ / Wellcome Trust / United Kingdom

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