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

Meri Kaustio¹, Naemeh Nayebzadeh², Reetta Hinttala², Terhi Tapiainen³, Pirjo Åström⁴, Katariina Mamia⁵, Nora Pernaa⁴, Johanna Lehtonen⁶, Virpi Glumoff⁴, Elisa Rahikkala⁷, Minna Honkila⁸, Päivi Olsén⁸, Antti Hassinen¹, Minttu Polso¹, Nashat Al Sukaiti⁹, Jalila Al Shekaili¹⁰, Mahmood Al Kindi¹⁰, Nadia Al Hashmi¹¹, Henrikki Almusa¹, Daria Bulanova¹², Emma Haapaniemi¹³, Pu Chen¹, Maria Suo-Palosaari¹⁴, Päivi Vieira⁸, Hannu Tuominen¹⁵, Hannaleena Kokkonen¹⁶, Nabil Al Macki¹⁷, Huda Al Habsi¹⁸, Tuija Löppönen¹⁹, Heikki Rantala²⁰, Vilja Pietiäinen¹, Shen-Ying Zhang²¹, Marjo Renko²², Timo Hautala²³, Tariq Al Farsi⁹, Johanna Uusimaa⁸, Janna Saarela²⁴

Affiliations

¹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
² PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center Oulu, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland.
³ PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center Oulu, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland.
⁴ Research Unit of Biomedicine, University of Oulu, Oulu, Finland.
⁵ Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway.
⁶ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway; Folkhälsan Research Center, Helsinki, Finland.
⁷ PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
⁸ PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland.
⁹ Department of Pediatric Allergy and Clinical Immunology, The Royal Hospital, Muscat, Oman.
¹⁰ Department of Microbiology and Immunology, Sultan Qaboos University Hospital, Muscat, Oman.
¹¹ Department of Clinical and Biochemical Genetics, The Royal Hospital, Muscat, Oman.
¹² Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
¹³ Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway; Department of Pediatric Research, Oslo University Hospital, Oslo, Norway; Research Programs Unit, Molecular Neurology and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁴ Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Diagnostic Radiology, Oulu University Hospital and University of Oulu, Oulu, Finland; Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁵ Department of Pathology, Oulu University Hospital, Oulu, Finland.
¹⁶ Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Clinical Genetics, Northern Finland Laboratory Centre, Oulu University Hospital, Oulu, Finland.
¹⁷ Department of Pediatric Neurology, The Royal Hospital, Muscat, Oman.
¹⁸ Department of General Pediatrics, The Royal Hospital, Muscat, Oman.
¹⁹ Department of Pediatrics, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
²⁰ PEDEGO Research Unit, University of Oulu, Oulu, Finland.
²¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Paris Descartes University, Imagine Institute, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France.
²² PEDEGO Research Unit, University of Oulu, Oulu, Finland; Department of Pediatrics, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
²³ Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.
²⁴ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland. Electronic address: janna.saarela@helsinki.fi.

PMID: 33662367
DOI: 10.1016/j.jaci.2020.12.656

Free article

Clinical Trial

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

Meri Kaustio et al. J Allergy Clin Immunol. 2021 Aug.

Free article

. 2021 Aug;148(2):599-611.

doi: 10.1016/j.jaci.2020.12.656. Epub 2021 Mar 1.

Authors

Affiliations

¹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
² PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center Oulu, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland.
³ PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center Oulu, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland.
⁴ Research Unit of Biomedicine, University of Oulu, Oulu, Finland.
⁵ Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway.
⁶ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway; Folkhälsan Research Center, Helsinki, Finland.
⁷ PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
⁸ PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland.
⁹ Department of Pediatric Allergy and Clinical Immunology, The Royal Hospital, Muscat, Oman.
¹⁰ Department of Microbiology and Immunology, Sultan Qaboos University Hospital, Muscat, Oman.
¹¹ Department of Clinical and Biochemical Genetics, The Royal Hospital, Muscat, Oman.
¹² Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
¹³ Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway; Department of Pediatric Research, Oslo University Hospital, Oslo, Norway; Research Programs Unit, Molecular Neurology and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁴ Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Diagnostic Radiology, Oulu University Hospital and University of Oulu, Oulu, Finland; Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁵ Department of Pathology, Oulu University Hospital, Oulu, Finland.
¹⁶ Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Clinical Genetics, Northern Finland Laboratory Centre, Oulu University Hospital, Oulu, Finland.
¹⁷ Department of Pediatric Neurology, The Royal Hospital, Muscat, Oman.
¹⁸ Department of General Pediatrics, The Royal Hospital, Muscat, Oman.
¹⁹ Department of Pediatrics, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
²⁰ PEDEGO Research Unit, University of Oulu, Oulu, Finland.
²¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Paris Descartes University, Imagine Institute, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France.
²² PEDEGO Research Unit, University of Oulu, Oulu, Finland; Department of Pediatrics, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
²³ Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.
²⁴ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland. Electronic address: janna.saarela@helsinki.fi.

PMID: 33662367
DOI: 10.1016/j.jaci.2020.12.656

Erratum in

Corrigenda.
[No authors listed] [No authors listed] J Allergy Clin Immunol. 2021 Dec;148(6):1603. doi: 10.1016/j.jaci.2021.09.002. J Allergy Clin Immunol. 2021. PMID: 34872653 No abstract available.

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 SCBMS pathogenesis.

Keywords: DIAPH1; SCBMS; T cells; immunodeficiency; microcephaly; mitochondrial dysfunction.

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

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LinkOut - more resources

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Medical