Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.
J Allergy Clin Immunol
; 148(2): 599-611, 2021 08.
Article
in En
| MEDLINE
| ID: mdl-33662367
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_005219c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219c.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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Seizures
/
Severe Combined Immunodeficiency
/
Blindness, Cortical
/
Mitochondrial Diseases
/
Formins
/
Microcephaly
Type of study:
Clinical_trials
/
Etiology_studies
Limits:
Adult
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Country/Region as subject:
Asia
/
Europa
Language:
En
Journal:
J Allergy Clin Immunol
Year:
2021
Document type:
Article
Affiliation country:
Finland