1. Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction
- Author
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Kaustio, M. (Meri), Nayebzadeh, N. (Naemeh), Hinttala, R. (Reetta), Tapiainen, T. (Terhi), Åström, P. (Pirjo), Mamia, K. (Katariina), Pernaa, N. (Nora), Lehtonen, J. (Johanna), Glumoff, V. (Virpi), Rahikkala, E. (Elisa), Honkila, M. (Minna), Olsén, P. (Päivi), Hassinen, A. (Antti), Polso, M. (Minttu), Al Sukaiti, N. (Nashat), Al Shekaili, J. (Jalila), Al Kindi, M. (Mahmood), Al Hashmi, N. (Nadia), Almusa, H. (Henrikki), Bulanova, D. (Daria), Haapaniemi, E. (Emma), Chen, P. (Pu), Suo-Palosaari, M. (Maria), Vieira, P. (Päivi), Tuominen, H. (Hannu), Kokkonen, H. (Hannaleena), Al Macki, N. (Nabil), Al Habsi, H. (Huda), Löppönen, T. (Tuija), Rantala, H. (Heikki), Pietiäinen, V. (Vilja), Zhang, S.-Y. (Shen-Ying), Renko, M. (Marjo), Hautala, T. (Timo), Al Farsi, T. (Tariq), Uusimaa, J. (Johanna), Saarela, J. (Janna), Kaustio, M. (Meri), Nayebzadeh, N. (Naemeh), Hinttala, R. (Reetta), Tapiainen, T. (Terhi), Åström, P. (Pirjo), Mamia, K. (Katariina), Pernaa, N. (Nora), Lehtonen, J. (Johanna), Glumoff, V. (Virpi), Rahikkala, E. (Elisa), Honkila, M. (Minna), Olsén, P. (Päivi), Hassinen, A. (Antti), Polso, M. (Minttu), Al Sukaiti, N. (Nashat), Al Shekaili, J. (Jalila), Al Kindi, M. (Mahmood), Al Hashmi, N. (Nadia), Almusa, H. (Henrikki), Bulanova, D. (Daria), Haapaniemi, E. (Emma), Chen, P. (Pu), Suo-Palosaari, M. (Maria), Vieira, P. (Päivi), Tuominen, H. (Hannu), Kokkonen, H. (Hannaleena), Al Macki, N. (Nabil), Al Habsi, H. (Huda), Löppönen, T. (Tuija), Rantala, H. (Heikki), Pietiäinen, V. (Vilja), Zhang, S.-Y. (Shen-Ying), Renko, M. (Marjo), Hautala, T. (Timo), Al Farsi, T. (Tariq), Uusimaa, J. (Johanna), and Saarela, J. (Janna)
- 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
- Published
- 2021