Publications
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Lehtonen, Johanna; Hakonen, Anna H; Hassinen, Antti; Lurås, Sanne Iversen; Kaustio, Meri & Glumoff, Virpi
[Show all 19 contributors for this article]
(2025).
Genome sequencing reveals CCDC88A variants in malformations of cortical development and immune dysfunction.
Human Molecular Genetics.
ISSN 0964-6906.
34(15),
p. 1294–1312.
doi:
10.1093/hmg/ddaf081.
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Abstract Malformations of cortical development (MCDs) encompass a diverse group of genetic and clinical disorders. Here, we aimed to determine a genetic etiology for two siblings manifesting MCD, microcephaly, epilepsy, intellectual disability, and susceptibility to infections. A missense variant (NM_018084:c.929A > C, p.Asp310Ala) and an intragenic deletion (exons 14–16) in CCDC88A were identified as compound heterozygous in patients by genome sequencing. Truncating homozygous CCDC88A variants are known to cause an ultra-rare syndrome manifesting with MCD, microcephaly, seizures, and severe neurological impairment. CCDC88A encodes girdin, which is essential for various cell functions, such as actin remodeling and cell proliferation. Western blot analysis showed that the missense variant allele was expressed in fibroblasts at a level compatible with a heterozygous allele, whereas a truncated protein from the deletion allele was barely detectable. Proliferation and wound-healing assays revealed that girdin-deficient fibroblasts proliferated faster and migrated slower than controls. High-content imaging highlighted girdin-deficient fibroblasts as smaller and their actin remodeling disrupted, leading to perinuclear accumulation of endolysosomal organelles. To confirm these cellular phenotypes resulted from girdin loss, CRISPR-Cas9 edited knockout models of healthy fibroblasts were created, replicating the observations in patient cells. Additionally, the siblings exhibited reduced monocytoid and plasmacytoid dendritic cells, suggesting compromised immunity due to girdin deficiency. In summary, the study describes the first case of a CCDC88A missense variant and intragenic deletion associated with MCD. It demonstrates altered immunity and girdin-related cellular changes, such as cell morphology and proliferation-migration dichotomy, in patient and knockout fibroblasts, reinforcing the pathogenic relevance of these variants.
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Pukaj, Albert; Harroud, Adil; Shchetynsky, Klementy; Wirsching, Laura; Peters, Lucy & Andlauer, Till F.M.
[Show all 52 contributors for this article]
(2025).
Genetic Risk Variants for Multiple Sclerosis and Other Loci Linked to Intrathecal Immunoglobulin G Synthesis.
Neurology: Neuroimmunology and neuroinflammation.
12(6).
doi:
10.1212/nxi.0000000000200499.
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Background and Objectives
Intrathecal synthesis of immunoglobulin G (IgG) is a key feature of multiple sclerosis (MS) and a prognostic marker for the disease course. Although previous studies identified 2 genetic regions—the major histocompatibility complex (MHC) region on chromosome 6 and the immunoglobulin heavy chain constant (IGHC) locus on chromosome 14—associated with intrathecal IgG synthesis in MS, the genetic underpinnings remain insufficiently understood.
Methods
We conducted a genome-wide association study on intrathecal IgG synthesis using the IgG index to identify individuals with (≥0.7) or without (<0.7) quantitative intrathecal synthesis. We used logistic regression models adjusting for sex, age, and population structure. We performed secondary analyses to examine associations between identified loci and the extent of intrathecal IgG synthesis and the presence and extent of intrathecal immunoglobulin A and M synthesis. We further conducted association analyses for imputed human leukocyte antigen alleles and analyzed whether a higher genetic burden for MS risk—quantified through polygenic risk scores—is associated with intrathecal IgG synthesis.
Results
In the discovery cohort (n = 3,934), we identified a novel genome-wide significant association of the intronic variant rs844586 (p = 1.48 × 10−8) in the sterile alpha motif domain containing 5 (SAMD5) gene on chromosome 6, with intrathecal IgG synthesis. We could confirm this association in a replication cohort (n = 1,094) and demonstrated that it is independent of a previously described association signal at the MHC region. In a subset (n = 1,413), we further identified rs1407 as a potential causal variant (p = 3.80 × 10−11, posterior inclusion probability = 0.92) for the previously reported association signal at the IGHC locus with the extent of intrathecal IgG synthesis. In addition, we demonstrated that a higher genetic burden for MS susceptibility, both within and outside of the MHC region, is associated with a higher likelihood of and a more pronounced intrathecal IgG synthesis.
Discussion
Our study revealed a previously unknown association between an intronic variant in SAMD5 with intrathecal IgG synthesis and identified a potential causal variant within the IGHC locus. It further provides evidence for possible effects of known MS risk variants on disease severity through their effect on the intrathecal humoral immune response, a prognostic marker for the disease course.
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Kalinichenko, Artem; Huemer, Jakob; Humer, Theresa; Haimel, Matthias; Svaton, Michael & Socquet-Juglard, Nicolas
[Show all 31 contributors for this article]
(2025).
Protein palmitoylation and sphingolipid metabolism control regulated exocytosis in cytotoxic lymphocytes.
Science immunology.
10(112).
doi:
10.1126/sciimmunol.ado3825.
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Regulated exocytosis controls key cellular functions ranging from neurotransmitter release to the secretion of immune mediators, and its disruption is associated with numerous pathologies. The cytotoxic activity of lymphocytes is particularly dependent on regulated and polarized lytic granule delivery toward infected or malignant cells. Although genetic and mechanistic studies have identified factors regulating exocytosis in cytotoxic lymphocytes, a systematic mapping of the relevant factors and their relationships is lacking. Through a genome-scale CRISPR knockout screen in a human natural killer cell line, we characterized a complex genetic network regulating cytotoxic granule exocytosis, with lipid metabolism and protein lipidation among the most prominent pathways. By combining global protein palmitoylation and lipidomic studies, we found that ZDHHC17 drives palmitoylation of the core SNARE complex protein SNAP23 to target cytotoxic granules to GM1-rich lipid rafts whose assembly is controlled by serine palmitoyltransferase. In summary, our study identifies previously unrecognized factors essential for cytotoxic function in human lymphocytes and uncovers how lipid metabolism and protein palmitoylation are involved in the process of regulated exocytosis.
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Mamia, Katariina Aino Inkeri; Kolbeinsdottir, Solrun; Labun, Kornel; Li, Zhuokun; Komisarczuk, Anna Zofia & Keskitalo, Salla
[Show all 32 contributors for this article]
(2025).
Precision T cell correction platform for Inborn Errors of Immunity.
Molecular Therapy.
ISSN 1525-0016.
33(11),
p. 5624–5643.
doi:
10.1016/j.ymthe.2025.08.018.
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CRISPR/Cas9 gene editing is a promising tool to correct pathogenic variants for autologous cell therapies targeting Inborn errors of immunity (IEI). Current strategies, such as gene knockout or cDNA knock-in, address many single-gene defects but can disrupt gene expression, highlighting the need for precise correction platforms. While transplanting corrected autologous hematopoietic stem cells is a curative approach, it is unsuitable for patients with advanced disease, inflammation or acute infections. As correcting T cells is an alternative therapeutic strategy for lymphoid IEIs, we present an efficient T cell single nucleotide variant (SNV) correction platform based on homology-directed repair (HDR). By using STAT1 gain-of-function (STAT1-GOF), Cartilage Hair Hypoplasia (CHH), Deficiency of ADA2 (DADA2), and Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as IEI models, we demonstrate that our platform achieves up to 80% correction, with resultant functional correction of the disease phenotype in the selected models. Furthermore, we performed safety profiling using GUIDE-seq, single-cell RNA sequencing, long-read genome sequencing, and proteomics analysis and detected no genomic, transcriptomic, or proteomic aberrations. This study establishes HDR-based SNV editing as a portable method for developing clinical autologous T cell therapies and represents a promising step toward a broad-spectrum gene correction platform for treating diverse monogenic immune disorders.
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Kaustio, Meri; Szymanska, Monika; Li, Weiwei; Braathen, Ragnhild Selvig; Campbell, Tessa M. & Haugen, Frida Loe
[Show all 23 contributors for this article]
(2025).
Heterozygous loss of MAP4K1 causes immune dysregulation by amplifying T-cell responses.
Journal of Allergy and Clinical Immunology.
ISSN 0091-6749.
156(4),
p. 1024–1037.
doi:
10.1016/j.jaci.2025.07.010.
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Background
MAP4K1 encodes hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase that negatively regulates T-cell receptor signaling via phosphorylation of the adaptor proteins SLP-76 (Src homology 2 domain-containing leukocyte protein of 76 kDa) and Gads. While common MAP4K1 variants have been implicated in polygenic immune-mediated diseases, the impact of rare germline variants on human immunity remains undefined.
Objective
We investigated the immunologic and functional consequences of HPK1 deficiency in individuals with suspected inborn errors of immunity.
Methods
We performed genomic linkage analysis and exome sequencing to identify disease-associated variants in patients with inborn errors of immunity. Immunophenotyping, RNA sequencing, and functional assays were conducted on patient-derived lymphocytes, complemented by CRISPR-Cas9–mediated MAP4K1 disruption and correction in primary T cells.
Results
Heterozygous MAP4K1 loss-of-function variants were identified in two kindreds presenting with diverse immune dysregulatory symptoms, including recurrent fevers, inflammatory arthritis, Epstein-Barr virus–related complications, and nephritis. These variants led to reduced HPK1 protein levels and SLP-76Ser376 phosphorylation. While lymphocyte development was largely preserved, T cells from HPK1-deficient individuals displayed hyperresponsiveness to T-cell receptor stimulation, characterized by elevated secretion of proinflammatory cytokines, particularly IFN-γ and TNF. CRISPR-Cas9–mediated knockout recapitulated, and variant correction partially reversed this phenotype. Transcriptomic profiling of stimulated CD4+ T cells further revealed upregulation of immune signaling pathways—including NF-κB, JAK/STAT, and AP-1—as well as increased expression of multiple T-cell cytokines, consistent with enhanced T-cell receptor signaling and T-cell responses in HPK1-deficient individuals.
Conclusion
HPK1 deficiency, caused by heterozygous loss of MAP4K1, is a novel monogenic cause of immune dysregulation. Increased T-cell activation and proinflammatory cytokine production are implicated in disease pathogenesis
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Nurmi, Katariina; Silventoinen, Kristiina; Keskitalo, Salla; Rajamäki, Kristiina; Kouri, Vesa-Petteri & Kinnunen, Matias
[Show all 32 contributors for this article]
(2024).
Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis.
Cell Reports Medicine.
5(4).
doi:
10.1016/j.xcrm.2024.101503.
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In monogenic autoinflammatory diseases, mutations in genes regulating innate immune responses often lead to uncontrolled activation of inflammasome pathways or the type I interferon (IFN-I) response. We describe a mechanism of autoinflammation potentially predisposing patients to life-threatening necrotizing soft tissue inflammation. Six unrelated families are identified in which affected members present with necrotizing fasciitis or severe soft tissue inflammations. Exome sequencing reveals truncating monoallelic loss-of-function variants of nuclear factor κ light-chain enhancer of activated B cells (NFKB1) in affected patients. In patients’ macrophages and in NFKB1-variant-bearing THP-1 cells, activation increases both interleukin (IL)-1β secretion and IFN-I signaling. Truncation of NF-κB1 impairs autophagy, accompanied by the accumulation of reactive oxygen species and reduced degradation of inflammasome receptor nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3), and Toll/IL-1 receptor domain-containing adaptor protein inducing IFN-β (TRIF), thus leading to combined excessive inflammasome and IFN-I activity. Many of the patients respond to anti-inflammatory treatment, and targeting IL-1β and/or IFN-I signaling could represent a therapeutic approach for these patients.
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Perälä, Miia; Kaustio, Meri; Salava, Alexander; Jakkula, Eveliina; Pelkonen, Anna S. & Saarela, Janna Saija
[Show all 8 contributors for this article]
(2023).
Relevance of Coding Variation in FLG And DOCK8 in Finnish Pediatric Patients with Early-Onset Moderate-To-Severe Atopic Dermatitis.
JID Innovations.
3(4).
doi:
10.1016/j.xjidi.2023.100203.
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Early-onset, persistent atopic dermatitis (AD) is proposed as a distinct subgroup that may have specific genotypic features. FLG gene loss-of-function variants are the best known genetic factors contributing to epidermal barrier impairment and eczema severity. In a cohort of 140 Finnish children with early-onset moderate-to-severe AD, we investigated the effect of coding variation in FLG and 13 other genes with epidermal barrier or immune function through the use of targeted amplicon sequencing and genotyping. A FLG loss-of-function variant (Arg501Ter, Ser761fs, Arg2447Ter, or Ser3247Ter) was identified in 20 of 140 patients showing higher transepidermal water loss values than patients without these variants. Total FLG loss-of-function variant frequency (7.14%) was significantly higher than in the general Finnish population (2.34%). When tested separately, only Arg2447Ter showed a significant association with AD (P = 0.003104). In addition, a modest association with moderate-to-severe pediatric AD was seen for rs12730241 and rs6587667 (FLG2:Gly137Glu). Loss-of-function variants, previously reported pathogenic variants, or statistically significant enrichment of nonsynonymous coding region variants were not found in the 13 candidate genes studied by amplicon sequencing. However, higher IgE and eosinophil counts were found in carriers of potentially pathogenic DOCK8 missense variants, suggesting that the role of DOCK8 variation in AD should be further investigated in larger cohorts.
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Santaniemi, Wenny; Åström, Pirjo; Glumoff, Virpi; Pernaa, Nora; Tallgren, Ella-Noora & Palosaari, Sanna
[Show all 14 contributors for this article]
(2023).
Inflammation and Neutrophil Oxidative Burst in a Family with NFKB1 p.R157X LOF and Sterile Necrotizing Fasciitis.
Journal of Clinical Immunology.
ISSN 0271-9142.
43,
p. 1007–1018.
doi:
10.1007/s10875-023-01461-3.
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Abstract Loss-of-function (LOF) mutations in NFKB1 , coding for p105, may cause common variable immunodeficiency due to dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κΒ) pathway. Monoallelic LOF variants of NFKB1 can predispose to uncontrolled inflammation including sterile necrotizing fasciitis or pyoderma gangrenosum. In this study, we explored the impact of a heterozygous NFKB1 c.C936T/p.R157X LOF variant on immunity in sterile fasciitis patients and their family members. The p50 or p105 protein levels were reduced in all variant carriers. Interleukin-1β (IL-1β) and interleukin-8 (IL-8) levels were elevated in vitro, potentially contributing to the very high neutrophil counts observed during fasciitis episodes. Phosphorylation of p65/RelA was reduced in p.R157X neutrophils suggesting defective activation of canonical NF-κB. Oxidative burst after NF-κB-independent phorbol 12-myristate 13-acetate (PMA) stimulation was similar in both p.R157X and control neutrophils. Comparable amounts of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex subunits were found in p.R157X and control neutrophils. However, a compromised oxidative burst was observed in p.R157X neutrophils following activation of NF-κB-dependent mechanisms following stimulation of toll-like receptor 2 (TLR2) and Dectin-1. Neutrophil extracellular trap formation was not affected by p.R157X. In summary, the NFKB1 c.C936T/p.R157X LOF variant has an impact on inflammation and neutrophil function and may play a role in the pathogenesis of sterile necrotizing fasciitis.
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Lee, Pui Y.; Davidson, Brad A.; Abraham, Roshini S.; Alter, Blanche; Arostegui, Juan I. & Bell, Katherine
[Show all 41 contributors for this article]
(2023).
Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement.
JAMA Network Open.
6(5),
p. e2315894–e2315894.
doi:
10.1001/jamanetworkopen.2023.15894.
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Importance Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. Objective To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. Evidence Review The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. Findings The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. Conclusions and Relevance DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.
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Brandt, E.; Harjama, L.; Elomaa, O.; Saarela, Janna Saija; Donner, K. & Lappalainen, K.
[Show all 11 contributors for this article]
(2023).
A novel SERPINA12 variant and first European patients with diffuse palmoplantar keratoderma.
Journal of the European Academy of Dermatology and Venereology.
ISSN 0926-9959.
doi:
10.1111/jdv.19498.
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Abstract Background Hereditary palmoplantar keratodermas (hPPKs) comprise a heterogeneous group of skin disorders characterized by persistent palmoplantar hyperkeratosis. Loss‐of‐function variants in a serine peptidase inhibitor, SERPINA12 , have recently been implicated in autosomal recessive diffuse hPPK. The disorder appears to share similarities with another hPPK associated with protease overactivity, namely Nagashima‐type PPK (NPPK) caused by biallelic variants in SERPINB7 . Objectives The aim of this study was to enhance the understanding of the clinical and genetic characteristics of serine protease‐related hPPKs caused by variants in SERPINA12 and SERPINB7 . Methods Whole‐exome sequencing (WES) was performed for hPPK patients. Haplotype analysis was completed for the patients with identified recessive SERPINA12 variants and their available family members. In addition, the current literature of SERPINA12 ‐ and SERPINB7 ‐related hPPKs was summarized. Results The phenotype of SERPINA12 ‐related hPPK was confirmed by reporting three new SERPINA12 patients, the first of European origin. A novel SERPINA12 c.1100G>A p.(Gly367Glu) missense variant was identified confirming that the variant spectrum of SERPINA12 include both truncating and missense variants. The previously reported SERPINA12 c.631C>T p.(Arg211*) was indicated enriched in the Finnish population due to a plausible founder effect. In addition, SERPINA12 hPPK patients were shown to share a similar phenotype to patients with recessive variants in SERPINB7 . The shared phenotype included diffuse transgradient PPK since birth or early childhood and frequent palmoplantar hyperhidrosis, aquagenic whitening and additional hyperkeratotic lesions in non‐palmoplantar areas. SERPINA12 and SERPINB7 hPPK patients cannot be distinguished without genetic analysis. Conclusions Recessive variants in SERPINA12 and SERPINB7 leading to protease overactivity and hPPK produce a similar phenotype, indistinguishable without genetic analysis. SERPINA12 variants should be assessed also in non‐Asian patients with diffuse transgradient PPK. Understanding the role of serine protease inhibitors will provide insights into the complex proteolytic network in epidermal homeostasis.
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Tuovinen, Elina A.; Kuismin, Outi; Soikkonen, Leila; Martelius, Timi; Kaustio, Meri & Hamalainen, Sari
[Show all 15 contributors for this article]
(2022).
Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae.
Clinical Immunology.
ISSN 1521-6616.
doi:
10.1016/j.clim.2022.109181.
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Nuclear factor κ light-chain enhancer of activated B cells (NF-κB) family of evolutionarily conserved transcription factors are involved in key cellular signaling pathways. Previously, hypogammaglobulinemia and common variable immunodeficiency (CVID)-like phenotypes have been associated with NFKB1 variants and loss-of-function NFKB1 variants have been reported as the most common monogenic cause for CVID among Europeans. Here, we describe a Finnish cohort of NFKB1 carriers consisting of 31 living subjects in six different families carrying five distinct heterozygous variants. In contrast to previous reports, the clinical penetrance was not complete even with advancing age and the prevalence of CVID/hypogammaglobulinemia was significantly lower, whereas (auto)inflammatory manifestations were more common (42% of the total cohort). At current stage of knowledge, routine genetic screening of asymptomatic individuals is not recommended, but counseling of potential adult carriers seems necessary.
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Goris, An; Vandebergh, Marijne; McCauley, Jacob L; Saarela, Janna Saija & Cotsapas, Chris
(2022).
Genetics of multiple sclerosis: lessons from polygenicity.
Lancet Neurology.
ISSN 1474-4422.
21(9),
p. 830–842.
doi:
10.1016/S1474-4422(22)00255-1.
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Large-scale mapping studies have identified 236 independent genetic variants associated with an increased risk of
multiple sclerosis. However, none of these variants are found exclusively in patients with multiple sclerosis. They are
located throughout the genome, including 32 independent variants in the MHC and one on the X chromosome. Most
variants are non-coding and seem to act through cell-specific effects on gene expression and splicing. The likely
functions of these variants implicate both adaptive and innate immune cells in the pathogenesis of multiple sclerosis,
provide pivotal biological insight into the causes and mechanisms of multiple sclerosis, and some of the variants
implicated in multiple sclerosis also mediate risk of other autoimmune and inflammatory diseases. Genetics offers
an approach to showing causality for environmental factors, through Mendelian randomisation. No single variant is
necessary or sufficient to cause multiple sclerosis; instead, each increases total risk in an additive manner. This
combined contribution from many genetic factors to disease risk, or polygenicity, has important consequences for
how we interpret the epidemiology of multiple sclerosis and how we counsel patients on risk and prognosis. Ongoing
efforts are focused on increasing cohort sizes, increasing diversity and detailed characterisation of study populations,
and translating these associations into an understanding of the biology of multiple sclerosis.
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Karvonen, V.; Harjama, L.; Heliö, K.; Kettunen, K.; Elomaa, O. & Koskenvuo, J.W.
[Show all 13 contributors for this article]
(2022).
A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign.
Journal of the European Academy of Dermatology and Venereology.
ISSN 0926-9959.
36(8),
p. 1349–1358.
doi:
10.1111/jdv.18164.
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Background
PPKs represent a heterogeneous group of disorders with hyperkeratosis of palmar and/or plantar skin. PPK, hair shaft abnormalities, cardiomyopathy and arrhythmias can be caused by mutations in desmosomal genes, e.g. desmoplakin (DSP). PPK should trigger genetic testing to reveal mutations with possible related cardiac disease.
Objectives
To report a large multigenerational family with a novel DSP mutation associated with early-onset PPK and adult-onset cardiomyopathy and arrhythmias.
Methods
A custom-designed in-house panel of 35 PPK related genes was used to screen mutations in the index patient with focal PPK. The identified DSP mutation was verified by Sanger sequencing. DNA samples from 20 members of the large multigenerational family were sequenced for the DSP mutation. Medical records were reviewed. Clinical dermatological evaluation was performed, including light microscopy of hair samples. Cardiac evaluation included clinical examination, echocardiography, cardiac magnetic resonance imaging (CMR), electrocardiogram (ECG), Holter monitoring and laboratory tests.
Results
We identified a novel autosomal dominant truncating DSP c.2493delA p.(Glu831Aspfs*33) mutation associated with dilated cardiomyopathy (DCM) with arrhythmia susceptibility and focal PPK as an early cutaneous sign. The mutation was found in nine affected family members, but not in any unaffected members. Onset of dermatological findings preceded cardiac symptoms which were variable and occurred at adult age.
Conclusions
We report a novel truncating DSP mutation causing focal PPK with varying severity and left ventricular dilatation and ventricular extrasystoles. This finding emphasizes the importance of genetic diagnosis in patients with PPK for clinical counselling and management of cardiomyopathies and arrhythmias.
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Kaustio, Meri; Nayebzadeh, Naemeh; Hinttala, Reetta; Tapiainen, Terhi; Åström, Pirjo & Mamia, Katariina Aino Inkeri
[Show all 37 contributors for this article]
(2021).
Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.
Journal of Allergy and Clinical Immunology.
ISSN 0091-6749.
148(2),
p. 599–611.
doi:
10.1016/j.jaci.2020.12.656.
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Background Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. Objective We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. Methods Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. Results Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients’ immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. Conclusions Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.
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Hetemäki, Iivo; Kaustio, Meri; Kinnunen, Matias; Heikkilä, Nelli; Keskitalo, Salla & Nowlan, Kirsten
[Show all 26 contributors for this article]
(2021).
Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells.
Science immunology.
6(65).
doi:
10.1126/sciimmunol.abe3454.
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The Ikaros family transcription factors regulate lymphocyte development. Loss-of-function variants in IKZF1 cause
primary immunodeficiency, but Ikaros family members IKZF2 and IKZF3 have not yet been associated with immunodeficiency. Here, we describe a pedigree with a heterozygous truncating variant in IKZF2, encoding the transcriptional
activator and repressor Helios, which is highly expressed in regulatory T cells and effector T cells, particularly of
the CD8+T cell lineage. Protein-protein interaction analysis revealed that the variant abolished heterodimerization
of Helios with Ikaros and Aiolos and also prevented Helios binding to members of the Mi-2/NuRD chromatin
remodeling complex. Patients carrying the IKZF2 variant presented with a combined immunodeficiency phenotype
characterized by recurrent upper respiratory infections, thrush and mucosal ulcers, and chronic lymphadenopathy.
With extensive immunophenotyping, functional assays, and transcriptional analysis, we show that reduced Helios
expression was associated with chronic T cell activation and increased production of proinflammatory cytokines
both in effector and regulatory T cells. Lymph node histology from patients indicated dysregulated germinal center
reactions. Moreover, affected individuals displayed a profound reduction in circulating MAIT cell numbers. In
summary, we show that this previously undescribed loss-of-function variant in Helios leads to an immunodeficiency
with signs of immune overactivation.
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Hashem, Hasan; Bucciol, Giorgia; Ozen, Seza; Unal, Sule; Bozkaya, Ikbal Ok & Akarsu, Nurten
[Show all 51 contributors for this article]
(2021).
Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.
Journal of Clinical Immunology.
ISSN 0271-9142.
doi:
10.1007/s10875-021-01098-0.
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Abstract Purpose Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. Methods We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). Results Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative ( n = 20), reduced intensity ( n = 8), or non-myeloablative ( n = 2). Donors were HLA-matched related ( n = 4), HLA-matched unrelated ( n = 16), HLA-haploidentical ( n = 2), or HLA-mismatched unrelated ( n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. Conclusion HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. Clinical Implications HCT is a definitive cure for DADA2 with > 95% survival.
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Savola, Paula; Martelius, Timi; Kankainen, Matti; Huuhtanen, Jani; Lundgren, Sofie & Koski, Yrjö
[Show all 16 contributors for this article]
(2021).
Somatic mutations and T-cell clonality in patients with immunodeficiency.
Haematologica.
ISSN 0390-6078.
doi:
10.3324/haematol.2019.220889.
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Common variable immunodeficiency and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is however implicated. To study whether somatic mutations in CD4+ and CD8+ T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset common variable immunodeficiency and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2533 immune-associated genes from CD4+ and CD8+ cells. Deep T-cell receptor beta sequencing was used to characterize CD4+ and CD8+ T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in common variable immunodeficiency and 48% in controls. Clonal hematopoiesis-associated variants in both CD4+ and CD8+ cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immune- and proliferative functions, such as STAT5B (two patients), C5AR1 (two patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, common variable immunodeficiency patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4+ and CD8+ cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.
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Cotsapas, Chris; Saarela, Janna Saija; Farmer, Jocelyn R.; Scaria, Vinod & Abraham, Roshini S.
(2021).
Do monogenic inborn errors of immunity cause susceptibility to severe COVID-19?
Journal of Clinical Investigation.
ISSN 0021-9738.
doi:
10.1172/JCI149459.
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Malani, Disha; Kumar, Kumar Adish; Brück, Oscar; Kontro, Mika; Yadav, Bhagwan & Hellesøy, Monica
[Show all 27 contributors for this article]
(2021).
Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia.
Cancer Discovery.
ISSN 2159-8274.
12.
doi:
10.1158/2159-8290.CD-21-0410.
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We generated ex vivo drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identification of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine. Significance: Oncogenomics data can guide clinical treatment decisions, but often such data are neither actionable nor predictive. Functional ex vivo drug testing contributes significant additional, clinically actionable therapeutic insights for individual patients with AML. Such data can be generated in four days, enabling rapid translation through FPMTB.
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Partanen, Terhi; Chen, Jie; Lehtonen, Johanna; Kuismin, Outi; Rusanen, Harri & Vapalahti, Olli
[Show all 21 contributors for this article]
(2020).
Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis.
Journal of Clinical Immunology.
ISSN 0271-9142.
40(8),
p. 1156–1156.
doi:
10.1007/s10875-020-00834-2.
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Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.
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Haugen, Frida Loe; Mamia, Katariina Aino Inkeri; Rio, Oline Eriksen; Sollano, Anniken Solveig Matheson; Li, Zhuokun & Labun, Kornel
[Show all 20 contributors for this article]
(2025).
CRISPR-Cas9 pipeline for custom editing in autologous T cells.
doi:
https:/event.fourwaves.com/crisprmed25/abstracts/b5911e8e-de8e-4ee4-b8e2-9f08cc2f31d8.
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CRISPR/Cas9 gene editing technology is a promising tool for correcting pathogenic variants in Inborn Errors of Immunity (IEIs). Current IEI correction strategies rely on cDNA knock-in or gene knockout, which can disrupt gene expression and need extensive optimization. To address this, we developed a safe, efficient CRISPR/Cas9-based T cell editing pipeline using HDR for SNV correction.
We observe a rapid and selective expansion of CD3+ T cells from patient peripheral blood following an 8-day cytokine stimulation. To enhance HDR outcomes, we explored multiple strategies and developed an optimized T cell pipeline capable of achieving up to 80% HDR. We found no pre-malignant off-target effects or karyotypic, transcriptomic, or proteomic abnormalities in patient T cells analysed with GUIDE-seq, scRNA-seq, long-read WGS, and proteomics. We observed functional correction of the disease phenotype in patient T cells demonstrated on transcriptomic level by single cell RNA sequencing, on proteomic level by Mass Spectrometry and in cell culture-based assays.
So far, we have implemented the pipeline and corrected 12 unique SNV mutations causing 8 diverse IEIs. This platform is designed to streamline CRISPR tool discovery/optimization and can be further developed into a GMP-compatible, scaled-up process for salvage therapy in T cell-related IEIs.
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Wang, Heling; Siow, Richard; Schmauck-Medina, Tomás Alejandro; Zhang, Jianying; Sandset, Per Morten & Filshie, Clare
[Show all 38 contributors for this article]
(2024).
Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies.
The journals of gerontology. Series A, Biological sciences and medical sciences.
ISSN 1079-5006.
79(4),
p. 1–10.
doi:
10.1093/gerona/glae029.
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Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.
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Hashem, Hasan; Bucciol, Giorgia; Ozen, Seza; Unal, Sule; Bozkaya, Ikbal Ok & Akarsu, Nurten
[Show all 51 contributors for this article]
(2022).
Correction to: Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients (Journal of Clinical Immunology, (2021), 41, 7, (1633-1647), 10.1007/s10875-021-01098-0).
Journal of Clinical Immunology.
ISSN 0271-9142.
doi:
10.1007/s10875-022-01280-y.
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Lehtonen, Johanna; Sulonen, Anna-Maija; Almusa, Henrikki & Saarela, Janna Saija
(2022).
Gaining long-read information synthetically using linked reads.
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Saarela, Janna Saija; Szymanska, Monika; Bøhn, Siv Kjølsrud & Lurås, Sanne Iversen
(2024).
Deciphering ADA2 Deficiency: Creating an ADA2 deficiency model using CRISPR/Cas genome editing.
Norges miljø- og biovitenskapelige universitet (NMBU).
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Mangel på adenosindeaminase 2 (DADA2) er en sjelden autoinflammatorisk lidelse forårsaket av bialleliske mutasjoner i adenosindeaminase 2 (ADA2) genet. Pasienter med DADA2 viser et bredt spekter av kliniske manifestasjoner, og tilstanden kan være livstruende. Sykdomsmekanismene til DADA2 er i stor grad ukjente og for å øke kunnskapen i dette feltet, hadde denne studien som mål å lage DADA2-cellemodeller og studere effekten av nedslått ADA2 genuttrykk på to sentrale immune celle mekanismer: proliferasjon av monocytter og makrofagpolarisering. For å gen redigere ADA2 ble guide RNA (gRNA) og CRISPR-assosiert protein 9 (Cas9) introdusert inn i THP-1 celler ved bruk av elektroporering. De gen redigerte cellene ble videre sortert ved bruk av fluorescensaktivert cellesortering (FACS), hvor til slutt fire av de utvalgte klonene viste en homozygot delesjon i ADA2-genet som er forventet å forårsake en leseramme forskyvning i budbringer-RNA (mRNA). En proliferasjon analyse som ble utført på ADA2-redigerte, ikke-sorterte celler ved bruk av Incucyte S3 viste at de redigerte cellene hadde en signifikant lavere proliferasjon sammenlignet med kontroll celler. Effekten av DADA2 på makrofagpolarisering ble testet på sorterte ADA2-redigerte celler og evaluert med spesifikke markører ved hjelp av kvantitativ PCR (qPCR). Cellene ble først differensiert til M0 og deretter polarisert til M1 og M2a makrofager. Resultatene indikerte at DADA2-cellemodeller viste en favorisert polarisering mot M1 makrofager. Eksperimentelle begrensninger oppsto, og ytterligere testing må gjøres for å trekke pålitelige konklusjoner.
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Published
Jan. 8, 2019 2:30 PM
- Last modified
June 30, 2025 1:07 PM
