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

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 BulanovaEmma 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)599-611
Number of pages13
JournalJournal of Allergy and Clinical Immunology
Issue number2
Publication statusPublished - Aug 2021


  • DIAPH1
  • T cells
  • immunodeficiency
  • microcephaly
  • mitochondrial dysfunction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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