Saettini, F;
Poli, C;
Vengoechea, J;
Bonanomi, S;
Orellana, JC;
Fazio, G;
Rodriguez, FH;
... Biondi, A; + view all
(2021)
Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in Folliculin Interacting Protein 1 deficiency.
Blood
, 137
(4)
pp. 493-499.
10.1182/blood.2020006441.
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Abstract
Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated three 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 PI3K/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy number variants [CNV] in two 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.
| Type: | Article |
|---|---|
| Title: | Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in Folliculin Interacting Protein 1 deficiency |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1182/blood.2020006441 |
| Publisher version: | https://doi.org/10.1182/blood.2020006441 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | agammaglobulinemia, b-lymphocytes, hypertrophic cardiomyopathy, animal model, neutropenia, 1-phosphatidylinositol 3-kinase, antibodies, recurrent infection, uniparental disomy, b cell development |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10111555 |
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