Early-Onset Diabetes in an Infant with a Novel Frameshift Mutation in LRBA

Galati, Alessio; Muciaccia, Rosalia; Marucci, Antonella; Paola, Rosa Di; Menzaghi, Claudia; Ortolani, Federica; Rutigliano, Alessandra; Rotondo, Arianna; Fischetto, Rita; Piccinno, Elvira; Delvecchio, Maurizio

doi:10.3390/ijerph191711031

Cited by 5 publications

(2 citation statements)

References 29 publications

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“…The key terms used in the search were LRBA in HGMD, LRBA deficiency, LRBA variants, LRBA clinical presentation, and LRBA only in PubMed and Scopus. The reports spanned from 2012 to 2023 1,2,4,16–19,21–59 (Table S1). Reports that included well‐specified variants and their associated phenotypes were also included.…”

Section: Methodsmentioning

confidence: 99%

Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation

Perez‐Perez,

Santos‐Argumedo,

Rodriguez‐Alba

et al. 2024

Pediatric Allergy Immunology

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LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early‐onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X‐linked‐like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease.

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Section: Methodsmentioning

confidence: 99%

Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation

Perez‐Perez,

Santos‐Argumedo,

Rodriguez‐Alba

et al. 2024

Pediatric Allergy Immunology

View full text Add to dashboard Cite

show abstract

“…LRBA is a ubiquitous protein whose functions have been described in immune, kidney, and neuronal cells. Since 2012, over 100 pathogenic variants of LRBA have been associated with common variable immunodeficiency ( 1 – 5 )as well as autoimmune disorders such as neonatal insulin-dependent diabetes mellitus (IDDM) ( 6 – 12 ), autoimmune lymphoproliferative syndrome (ALPS)-like syndrome ( 1 , 3 , 13 ), immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX)-like syndrome ( 1 , 3 , 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-responsive beige-like anchor is involved in regulating NF-κB activation in B cells

Pérez-Pérez,

Fuentes-Pananá,

Flores-Hermenegildo

et al. 2024

Front. Immunol.

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IntroductionLipopolysaccharide-responsive and beige-like anchor (LRBA) is a scaffolding protein that interacts with proteins such as CTLA-4 and PKA, the importance of which has been determined in various cell types, including T regulatory cells, B cells, and renal cells. LRBA deficiency is associated with an inborn error in immunity characterized by immunodeficiency and autoimmunity. In addition to defects in T regulatory cells, patients with LRBA deficiency also exhibit B cell defects, such as reduced cell number, low memory B cells, hypogammaglobulinemia, impaired B cell proliferation, and increased autophagy. Although Lrba-/- mice do not exhibit the immunodeficiency observed in humans, responses to B cell receptors (BCR) in B cells have not been explored. Therefore, a murine model is for elucidating the mechanism of Lrba mechanism in B cells.AimTo compare and evaluate spleen-derived B cell responses to BCR crosslinking in C57BL6 Lrba-/- and Lrba+/+ mice.Materials and methodsSpleen-derived B cells were obtained from 8 to 12-week-old mice. Subpopulations were determined by immunostaining and flow cytometry. BCR crosslinking was assessed by the F(ab’)2 anti-μ chain. Activation, proliferation and viability assays were performed using flow cytometry and protein phosphorylation was evaluated by immunoblotting. The nuclear localization of p65 was determined using confocal microscopy. Nur77 expression was evaluated by Western blot.ResultsLrba-/- B cells showed an activated phenotype and a decreased proportion of transitional 1 B cells, and both proliferation and survival were affected after BCR crosslinking in the Lrba-/- mice. The NF-κB pathway exhibited a basal activation status of several components, resulting in increased activation of p50, p65, and IκBα, basal p50 activation was reduced by the Plcγ2 inhibitor U73122. BCR crosslinking in Lrba-/- B cells resulted in poor p50 phosphorylation and p65 nuclear localization. Increased levels of Nur77 were detected.DiscussionThese results indicate the importance of Lrba in controlling NF-κB activation driven by BCR. Basal activation of NF-κB could impact cellular processes, such as, activation, differentiation, proliferation, and maintenance of B cells after antigen encounter.

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Neonatal diabetes mellitus around the world: Update 2024

Barbetti,

Deeb,

Suzuki

2024

J of Diabetes Invest

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Neonatal diabetes mellitus (NDM), defined as diabetes with an onset during the first 6 months of life, is a rare form of monogenic diabetes. The initial publications on this condition began appearing in the second half of the 1990s and quite surprisingly, the search for new NDM genes is still ongoing with great vigor. Between 2018 and early 2024, six brand new NDM‐genes have been discovered (CNOT1, FICD, ONECUT1, PDIA6, YIPF5, ZNF808) and three genes known to cause different diseases were identified as NDM‐genes (EIF2B1, NARS2, KCNMA1). In addition, NDM cases carrying mutations in three other genes known to give rise to diabetes during childhood have been also identified (AGPAT2, BSCL2, PIK3R1). As a consequence, the list of NDM genes now exceeds 40. This genetic heterogeneity translates into many different mechanism(s) of disease that are being investigated with state‐of‐the‐art methodologies, such as induced pluripotent stem cells (iPSC) and human embryonic stem cells (hESC) manipulated with the CRISPR technique of genome editing. This diversity in genetic causes and the pathophysiology of diabetes dictate the need for a variety of therapeutic approaches. The aim of this paper is to provide an overview on recent achievements in all aspects of this area of research.

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Early-Onset Diabetes in an Infant with a Novel Frameshift Mutation in LRBA

Cited by 5 publications

References 29 publications

Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation

Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation

Lipopolysaccharide-responsive beige-like anchor is involved in regulating NF-κB activation in B cells

Neonatal diabetes mellitus around the world: Update 2024

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