Meri Kaustio, Naemeh Nayebzadeh, Reetta Hinttala, Terhi Tapiainen, Pirjo Åström, Katariina Mamia, Nora Pernaa, Johanna Lehtonen, Virpi Glumoff, Elisa Rahikkala, Minna Honkila, Päivi Olsén, Antti Hassinen, Minttu Polso, Nashat Al Sukaiti, Jalila Al Shekaili, Mahmood Al Kindi, Nadia Al Hashmi, Henrikki Almusa, Daria Bulanova, Emma Haapaniemi, Pu Chen, Maria Suo-Palosaari, Päivi Vieira, Hannu Tuominen, Hannaleena Kokkonen, Nabil Al Macki, Huda Al Habsi, Tuija Löppönen, Heikki Rantala, Vilja Pietiäinen, Shen-Ying Zhang, Marjo Renko, Timo Hautala, Tariq Al Farsi, Johanna Uusimaa, Janna Saarela, Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction, Journal of Allergy and Clinical Immunology, Volume 148, Issue 2, 2021, Pages 599-611, ISSN 0091-6749, https://doi.org/10.1016/j.jaci.2020.12.656
Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction
|Author:||Kaustio, Meri1; Nayebzadeh, Naemeh2,3,4; Hinttala, Reetta2,3,4;|
1Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
2PEDEGO Research Unit, University of Oulu, Oulu, Finland
3Medical Research Center Oulu, University of Oulu, Oulu, Finland
4Biocenter Oulu, Oulu, Finland
5Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland
6Research Unit of Biomedicine, University of Oulu, Oulu, Finland
7Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway
8Folkhälsan Research Center, Helsinki, Finland
9Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
10Department of Pediatric Allergy and Clinical Immunology, The Royal Hospital, Muscat, Oman
11Department of Microbiology and Immunology, Sultan Qaboos University Hospital, Muscat, Oman
12Department of Clinical and Biochemical Genetics, The Royal Hospital, Muscat, Oman
13Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
14Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
15Research Programs Unit, Molecular Neurology and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland
16Department of Diagnostic Radiology, Oulu University Hospital and University of Oulu, Oulu, Finland
17Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland
18Department of Pathology, Oulu University Hospital, Oulu, Finland
19Department of Clinical Genetics, Northern Finland Laboratory Centre, Oulu University Hospital, Oulu, Finland
20Department of Pediatric Neurology, The Royal Hospital, Muscat, Oman
21Department of General Pediatrics, The Royal Hospital, Muscat, Oman
22Department of Pediatrics, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
23St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
24Paris Descartes University, Imagine Institute, Paris, France
25Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France
26Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
27Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
28Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland
|Online Access:||PDF Full Text (PDF, 3.1 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2021112456744
|Publish Date:|| 2021-11-24
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.
Journal of allergy and clinical immunology
|Pages:||599 - 611|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
© 2021 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0).