دورية أكاديمية
Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction
| العنوان: | Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction |
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| المؤلفون: | Kaustio, Meri, Nayebzadeh, Naemeh, Hinttala, Reetta, Tapiainen, Terhi, Åström, Pirjo, Mamia, Katariina, Pernaa, Nora, Lehtonen, Johanna, Glumoff, Virpi, Rahikkala, Elisa, Honkila, Minna, Olsén, Päivi, Hassinen, Antti, Polso, Minttu, Al Sukaiti, Nashat, Al Shekaili, Jalila, Al Kindi, Mahmood, Al Hashmi, Nadia, Almusa, Henrikki, Bulanova, Daria, Haapaniemi, Emma, Chen, Pu, Suo-Palosaari, Maria, Vieira, Päivi, Tuominen, Hannu, Kokkonen, Hannaleena, Al Macki, Nabil, Al Habsi, Huda, Löppönen, Tuija, Rantala, Heikki, Pietiäinen, Vilja, Zhang, Shen Ying, Renko, Marjo, Hautala, Timo, Al Farsi, Tariq, Uusimaa, Johanna, Saarela, Janna |
| المصدر: | Kaustio , M , Nayebzadeh , N , Hinttala , R , Tapiainen , T , Åström , P , Mamia , K , Pernaa , N , Lehtonen , J , Glumoff , V , Rahikkala , E , Honkila , M , Olsén , P , Hassinen , A , Polso , M , Al Sukaiti , N , Al Shekaili , J , Al Kindi , M , Al Hashmi , N , Almusa , H , Bulanova , D , Haapaniemi , E , Chen , P , Suo-Palosaari , M , Vieira , P .... |
| سنة النشر: | 2021 |
| المجموعة: | University of Copenhagen: Research / Forskning ved Københavns Universitet |
| مصطلحات موضوعية: | DIAPH1, immunodeficiency, microcephaly, mitochondrial dysfunction, SCBMS, T cells |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| DOI: | 10.1016/j.jaci.2020.12.656 |
| الإتاحة: | https://doi.org/10.1016/j.jaci.2020.12.656Test https://curis.ku.dk/portal/da/publications/loss-of-diaph1-causes-scbms-combined-immunodeficiency-and-mitochondrial-dysfunctionTest(dfcd7940-6c75-4d8a-9900-f9c683337e88).html https://curis.ku.dk/ws/files/279141525/1_s2.0_S0091674921003456_main.pdfTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.FC89EA56 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.jaci.2020.12.656 |
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