TY - JOUR

T1 - Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction

AU - Kaustio, Meri

AU - Nayebzadeh, Naemeh

AU - Hinttala, Reetta

AU - Tapiainen, Terhi

AU - Åström, Pirjo

AU - Mamia, Katariina

AU - Pernaa, Nora

AU - Lehtonen, Johanna

AU - Glumoff, Virpi

AU - Rahikkala, Elisa

AU - Honkila, Minna

AU - Olsén, Päivi

AU - Hassinen, Antti

AU - Polso, Minttu

AU - Al Sukaiti, Nashat

AU - Al Shekaili, Jalila

AU - Al Kindi, Mahmood

AU - Al Hashmi, Nadia

AU - Almusa, Henrikki

AU - Bulanova, Daria

AU - Haapaniemi, Emma

AU - Chen, Pu

AU - Suo-Palosaari, Maria

AU - Vieira, Päivi

AU - Tuominen, Hannu

AU - Kokkonen, Hannaleena

AU - Al Macki, Nabil

AU - Al Habsi, Huda

AU - Löppönen, Tuija

AU - Rantala, Heikki

AU - Pietiäinen, Vilja

AU - Zhang, Shen Ying

AU - Renko, Marjo

AU - Hautala, Timo

AU - Al Farsi, Tariq

AU - Uusimaa, Johanna

AU - Saarela, Janna

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - DIAPH1

KW - immunodeficiency

KW - microcephaly

KW - mitochondrial dysfunction

KW - SCBMS

KW - T cells

U2 - 10.1016/j.jaci.2020.12.656

DO - 10.1016/j.jaci.2020.12.656

M3 - Journal article

C2 - 33662367

AN - SCOPUS:85104134872

VL - 148

SP - 599

EP - 611

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 2

ER -