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

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Neuroscience
• Mitochondrial Biology

Background:

• Homozygous loss of the DIAPH1 gene results in Seizures, Cortical Blindness, and Microcephaly Syndrome (SCBMS).
• Patients with DIAPH1 loss exhibit SCBMS, mitochondrial dysfunction, and immunodeficiency.

Purpose of the Study:

• To further characterize the clinical phenotypes associated with DIAPH1 loss.
• To investigate the underlying disease mechanisms, including immune and mitochondrial dysfunction.

Main Methods:

• Exome sequencing and genetic analyses to identify DIAPH1 variants.
• B- and T-cell phenotyping, lymphocyte stimulation assays, and immunofluorescence.
• Mitochondrial function analyses and CRISPR-Cas9 gene editing in patient-derived cells.

Main Results:

• Identified homozygous DIAPH1 variants in Finnish and Omani patients with SCBMS.
• Patients presented with infection susceptibility, defective lymphocyte maturation, and B-cell lymphoma.
• Demonstrated impaired T-cell function, cytoskeletal defects, and mitochondrial complex IV dysfunction.

Conclusions:

• Individuals with SCBMS can exhibit combined immune deficiency.
• Defective cytoskeletal organization and mitochondrial dysfunction are implicated in SCBMS pathogenesis.
• DIAPH1 plays a crucial role in immune cell function and mitochondrial health.