Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Kaustio Meri, Nayebzadeh Naemeh, Hinttala Reetta, Tapiainen Terhi, Åström Pirjo, Mamia Katariina, Pernaa Nora, Lehtonen Johanna, Glumoff Virpi, Rahikkala Elisa, Honkila Minna, Olsén Päivi, 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 Päivi, 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
Аннотация
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.