Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy

Sharma, Mehul; Fu, Maggie P; Lu, Henry Y.; Sharma, Ashish; Modi, Bhavi P.; Michalski, Christina; Lin, Susan; Dalmann, Joshua; Salman, Areesha; Bel, Kate L. Del; Waqas, Meriam A.; Terry, Jefferson; Setiadi, Audi; Lavoie, Pascal M.; Wasserman, Wyeth W.; Mwenifumbo, Jill; Kobor, Michæl S.; Lee, Anna F.; Kuchenbauer, Florian; Lehman, Anna; Cheng, Sylvia; Cooper, Anthony; Patel, Millan S.

doi:10.1182/blood.2022015674

Cited by 10 publications

(11 citation statements)

References 75 publications

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“…Immunophenotyping and intracellular cytokine was performed as previously described 30 . Briefly, PBMCs were stimulated with PMA and ionomycin (P/I) in the presence of GolgiStop (#554724, BD Biosciences), stained with antibody panels 1-4 ( Supplemental Table 5 ) using the eBioscience Foxp3 Transcription Factor Staining Buffer Set (#00-5523-00, Invitrogen, ThermoFisher), acquired on a FACSymphony flow cytometer, and analyzed using FlowJo (both BD Biosciences) ( Supplement ).…”

Section: Methodsmentioning

confidence: 99%

“…Single-cell RNA sequencing was performed on unstimulated and 4h P/I-stimulated sorted Tregs and Tconv from P1 and two age-matched/sex-matched controls using the BD Rhapsody Single Cell platform (BD Biosciences) according to manufacturer’s recommendations and analyzed as previously described 30 ( Supplement ). Raw data are deposited on Gene Expression Omnibus.…”

Section: Methodsmentioning

confidence: 99%

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A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD

Lu,

Vaseghi-Shanjani,

Lam

et al. 2023

Preprint

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Monogenic defects that impair the control of inflammation and tolerance lead to profound immune dysregulation, including autoimmunity and atopy. Studying these disorders reveals important molecular and cellular factors that regulate human immune homeostasis and identifies potential precision medicine targets. Here, we provide a detailed immunological assessment of a pediatric patient with a recently discovered syndrome causing Immunodysregulation, Craniofacial anomalies, Hearing impairment, Athelia, and Developmental delay (or ICHAD syndrome). The immunodysregulation resulted in autoimmune hemolytic anemia (AIHA) and atopic dermatitis. The patient carried ade novogermline heterozygous c.406+540_574+13477dup;p.Gly136_Ser191dup variant inIKAROS family zinc finger 2(IKZF2), which encodes Helios. This variant led to reduced Helios protein expression and dominant interference of wild-type Helios-mediated repression of theIL2promoter. Multi-parameter flow cytometric analyses of patient peripheral blood mononuclear cells revealed strongly impaired natural killer cell differentiation and function, and increased CD8+T cell activation and cytokine secretion. Strikingly, patient CD4+T cells were hyperactive, produced elevated levels of nearly all T helper (TH) cytokines, and readily proliferated in response to stimulation. Patient regulatory T cells (Tregs) developed normally but aberrantly produced high levels of many THcytokines. Single-cell RNA sequencing revealed largely normal Tregs (albeit mostly memory), but naïve CD4+T cells that were more enriched in genes related to activation, proliferation, metabolism, and THdifferentiation. This work describes the immunological phenotype of one of the first reported cases of germline dominant negative Helios deficiency, expands our understanding of the pathogenesis of AIHA on a single cell level, and provides valuable insights into Helios function in a variety of lymphocyte subsets.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD

Lu,

Vaseghi-Shanjani,

Lam

et al. 2023

Preprint

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“…a Includes asthma, childhood-onset asthma, adult-onset asthma, and atopic asthma. healthy controls, to study CD4 + T helper subsets as previously described (Sharma et al, 2022). (c) CD23 and IL-4Rα expression was studied on seven patient PBMCs and nine healthy control PBMCs.…”

Section: Luciferase Reporter Assaysmentioning

confidence: 99%

“…Immunoblotting was conducted as previously described (Sharma et al, 2022) to assess the phosphorylation status of p.P643R STAT6 variant, as phosphorylation of this variant could not be detected via flow cytometry, using an antibody against the tyrosine 641 phosphorylation site. See supplemental methods at the end of the PDF for details.…”

Section: Immunoblottingmentioning

confidence: 99%

Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease

Sharma

Leung

Momenilandi

et al. 2023

Journal of Experimental Medicine

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STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

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“…While animal models are often used to validate the clinical phenotypes observed in patients with RDEOs and validate the genotype–phenotype associations ( Cacheiro et al, 2019 ), they can also be informative regarding potential disease progression. One example outside of RDEO is the report of B-cell malignancy in aging Nfatc2 knockout (KO) mice before the discovery of the first human patient with homozygous LoF NFATC2 variant, who developed B-cell lymphoma as a young adult ( May et al, 2014 ; Sharma et al, 2022 ). Previous Nfatc2 KO mouse studies mainly focused on skeletal and cartilage defects, as these symptoms manifest early ( Ranger et al, 2000 ; Koga et al, 2005 ).…”

Section: Challenges and Opportunities In Studying Rdeosmentioning

confidence: 99%

Rare diseases of epigenetic origin: Challenges and opportunities

Merrill

Sharma

et al. 2023

Front. Genet.

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Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace of discovery of novel RDs and provided more accurate means for their diagnosis. RDs that are driven by altered epigenetic regulation with an underlying genetic basis are referred to as rare diseases of epigenetic origin (RDEOs). These diseases pose unique challenges in research, as they often show complex genetic and clinical heterogeneity arising from unknown gene–disease mechanisms. Furthermore, multiple other factors, including cell type and developmental time point, can confound attempts to deconvolute the pathophysiology of these disorders. These challenges are further exacerbated by factors that contribute to epigenetic variability and the difficulty of collecting sufficient participant numbers in human studies. However, new molecular and bioinformatics techniques will provide insight into how these disorders manifest over time. This review highlights recent studies addressing these challenges with innovative solutions. Further research will elucidate the mechanisms of action underlying unique RDEOs and facilitate the discovery of treatments and diagnostic biomarkers for screening, thereby improving health trajectories and clinical outcomes of affected patients.

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Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy

Cited by 10 publications

References 75 publications

A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD

A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD

Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease

Rare diseases of epigenetic origin: Challenges and opportunities

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