Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction

Show full item record




Kaustio , M , Nayebzadeh , N , Hinttala , R , Tapiainen , T , Astrom , P , Mamia , K , Pernaa , N , Lehtonen , J , Glumoff , V , Rahikkala , E , Honkila , M , Olsen , 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 , Tuominen , H , Kokkonen , H , Al Macki , N , Al Habsi , H , Löppönen , T , Rantala , H , Pietiäinen , V , Zhang , S-Y , Renko , M , Hautala , T , Al Farsi , T , Uusimaa , J & Saarela , J 2021 , ' Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction ' , Journal of Allergy and Clinical Immunology , vol. 148 , no. 2 , pp. 599-611 . https://doi.org/10.1016/j.jaci.2020.12.656

Title: Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction
Author: Kaustio, Meri; Nayebzadeh, Naemeh; Hinttala, Reetta; Tapiainen, Terhi; Astrom, Pirjo; Mamia, Katariina; Pernaa, Nora; Lehtonen, Johanna; Glumoff, Virpi; Rahikkala, Elisa; Honkila, Minna; Olsen, Paivi; 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, 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
Contributor organization: Institute for Molecular Medicine Finland
Helsinki Institute of Life Science HiLIFE
Precision Systems Medicine
STEMM - Stem Cells and Metabolism Research Program
Research Programs Unit
Janna Saarela / Principal Investigator
Date: 2021-08
Language: eng
Number of pages: 13
Belongs to series: Journal of Allergy and Clinical Immunology
ISSN: 0091-6749
DOI: https://doi.org/10.1016/j.jaci.2020.12.656
URI: http://hdl.handle.net/10138/335007
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.68411G>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.
Subject: DIAPH1
mitochondrial dysfunction
T cells
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: publishedVersion

Files in this item

Total number of downloads: Loading...

Files Size Format View
PIIS0091674921003456.pdf 3.052Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record