dc.date.accessioned | 2022-02-15T16:45:55Z | |
dc.date.available | 2022-02-15T16:45:55Z | |
dc.date.created | 2022-01-25T11:36:54Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | Kaustio, Meri Nayebzadeh, Naemeh Hinttala, Reetta Tapiainen, Terhi Åström, Pirjo Mamia, Katariina Aino Inkeri Pernaa, Nora Lehtonen, Johanna Marianna Glumoff, Virpi Rahikkala, Elisa Honkila, Minna Olsén, Päivi Hassinen, Antti Polso, Minttu Al Sukati, Nashat Al Shekaili, Jalila Al Kindi, Mahmood Al Hashmi, Nadia Almusa, Henrikki Bulanova, Daria Haapaniemi, Emma Maria Chen, Pu Suo-Palosaari, Maria Vieira, Paivi 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 Saija . Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction. Journal of Allergy and Clinical Immunology. 2021 | |
dc.identifier.uri | http://hdl.handle.net/10852/90982 | |
dc.description.abstract | 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. | |
dc.language | EN | |
dc.publisher | American Academy of Allergy, Asthma and Immunology | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.title | Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction | |
dc.type | Journal article | |
dc.creator.author | Kaustio, Meri | |
dc.creator.author | Nayebzadeh, Naemeh | |
dc.creator.author | Hinttala, Reetta | |
dc.creator.author | Tapiainen, Terhi | |
dc.creator.author | Åström, Pirjo | |
dc.creator.author | Mamia, Katariina Aino Inkeri | |
dc.creator.author | Pernaa, Nora | |
dc.creator.author | Lehtonen, Johanna Marianna | |
dc.creator.author | Glumoff, Virpi | |
dc.creator.author | Rahikkala, Elisa | |
dc.creator.author | Honkila, Minna | |
dc.creator.author | Olsén, Päivi | |
dc.creator.author | Hassinen, Antti | |
dc.creator.author | Polso, Minttu | |
dc.creator.author | Al Sukati, Nashat | |
dc.creator.author | Al Shekaili, Jalila | |
dc.creator.author | Al Kindi, Mahmood | |
dc.creator.author | Al Hashmi, Nadia | |
dc.creator.author | Almusa, Henrikki | |
dc.creator.author | Bulanova, Daria | |
dc.creator.author | Haapaniemi, Emma Maria | |
dc.creator.author | Chen, Pu | |
dc.creator.author | Suo-Palosaari, Maria | |
dc.creator.author | Vieira, Paivi | |
dc.creator.author | Tuominen, Hannu | |
dc.creator.author | Kokkonen, Hannaleena | |
dc.creator.author | Al Macki, Nabil | |
dc.creator.author | Al Habsi, Huda | |
dc.creator.author | Löppönen, Tuija | |
dc.creator.author | Rantala, Heikki | |
dc.creator.author | Pietiäinen, Vilja | |
dc.creator.author | Zhang, Shen-Ying | |
dc.creator.author | Renko, Marjo | |
dc.creator.author | Hautala, Timo | |
dc.creator.author | Al Farsi, Tariq | |
dc.creator.author | Uusimaa, Johanna | |
dc.creator.author | Saarela, Janna Saija | |
cristin.unitcode | 185,57,19,0 | |
cristin.unitname | Saarela group - Human immune disorders | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 1989338 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Journal of Allergy and Clinical Immunology&rft.volume=&rft.spage=&rft.date=2021 | |
dc.identifier.jtitle | Journal of Allergy and Clinical Immunology | |
dc.identifier.volume | 148 | |
dc.identifier.issue | 2 | |
dc.identifier.startpage | 599 | |
dc.identifier.endpage | 611 | |
dc.identifier.doi | https://doi.org/10.1016/j.jaci.2020.12.656 | |
dc.identifier.urn | URN:NBN:no-93573 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 0091-6749 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/90982/1/1-s2.0-S0091674921003456-main.pdf | |
dc.type.version | PublishedVersion | |
dc.relation.project | NFR/187615 | |