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

Journal
Blood
ISSN
0006-4971
1528-0020
Date Issued
2021
Author(s)
Francesco Saettini
Jaime Vengoechea
Sonia Bonanomi
Julio C. Orellana
Grazia Fazio
Fred H. Rodriguez
Loreani P. Noguera
Claire Booth
Valentina Jarur-Chamy
Marissa Shams
Maria Iascone
Maja Vukic
Serena Gasperini
Manuel Quadri
Amairelys Barroeta Seijas
Elizabeth Rivers
Mario Mauri
Raffaele Badolato
Gianni Cazzaniga
Cristina Bugarin
Giuseppe Gaipa
Wilma G. M. Kroes
Daniele Moratto
Monique M. van Oostaijen-ten Dam
Frank Baas
Silvère van der Maarel
Rocco Piazza
Zeynep H. Coban-Akdemir
James R. Lupski
Bo Yuan
Ivan K. Chinn
Lucia Daxinger
Andrea Biondi
Type
Resource Types::text::journal::journal article
Scopus ID
2-s2.0-85097774825
WoS ID
WOS:000614138100012
DOI
URL
URL Institutional Repository
Abstract
<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>
Cite this document
Saettini, F., Poli, C., Vengoechea, J., Bonanomi, S., Orellana, J. C., Fazio, G., Rodriguez, F. H., Noguera, L. P., Booth, C., Jarur-Chamy, V., Shams, M., Iascone, M., Vukic, M., Gasperini, S., Quadri, M., Barroeta Seijas, A., Rivers, E., Mauri, M., Badolato, R., … Biondi, A. (2021). Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency. Blood, 137(4), 493-499. https://doi.org/10.1182/blood.2020006441
Project(s)
Subjects
fnip1

; 

ampk

; 

pathway

; 

adult

; 

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

; 

folliculin interacting protein 1

; 

immunoglobulin

; 

immunoglobulin a

; 

immunoglobulin e

; 

immunoglobulin g

; 

immunoglobulin m

; 

messenger rna

; 

phosphatidylinositol 3 kinase

; 

protein

; 

protein kinase b

; 

s6 kinase

; 

tubulin

; 

unclassified drug

; 

carrier protein

; 

fnip1 protein, human

; 

fnip1 protein, mouse

; 

adult

; 

agammaglobulinemia

; 

animal cell

; 

animal experiment

; 

animal model

; 

animal tissue

; 

article

; 

b lymphocyte

; 

case report

; 

cell metabolism

; 

chromosome 5

; 

clinical article

; 

copy number variation

; 

enzyme phosphorylation

; 

female

; 

folliculin interacting protein 1 deficiency

; 

heart preexcitation

; 

heterozygote

; 

homozygote

; 

human

; 

hypertrophic cardiomyopathy

; 

immune deficiency

; 

immunotherapy

; 

male

; 

mitochondrion

; 

mouse

; 

neutropenia

; 

neutrophil count

; 

nonhuman

; 

nuclear magnetic resonance imaging

; 

phenotype

; 

pi3k/akt signaling

; 

pre b lymphocyte

; 

priority journal

; 

sanger sequencing

; 

single nucleotide polymorphism

; 

uniparental disomy

; 

whole exome sequencing

; 

agammaglobulinemia

; 

animal

; 

b lymphocyte

; 

child

; 

congenital heart malformation

; 

consanguinity

; 

crohn disease

; 

developmental disorder

; 

disease model

; 

disease predisposition

; 

etiology

; 

genetics

; 

hypertrophic cardiomyopathy

; 

immune deficiency

; 

loss of function mutation

; 

lymphocytopenia

; 

metabolism

; 

pathology

; 

pedigree

; 

preschool child

; 

stop codon