Rescue of recurrent deep intronic mutation underlying cell type-dependent quantitative NEMO deficiency

Area of Science:

• Genetics
• Molecular Biology
• Immunology

Background:

• Incontinentia Pigmenti (IP) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) are linked to IKBKG (NEMO) gene mutations.
• Loss-of-function and hypomorphic mutations in IKBKG cause distinct clinical phenotypes.

Observation:

• Two mothers, one with mild IP and one without, had sons with fatal EDA-ID.
• The same deep intronic IKBKG variant, IVS4+866 C>T, was identified in affected families.
• This variant creates a pseudoexon, leading to frameshift and impaired NF-κB activation.

Findings:

• Aberrant splicing rates of the IKBKG pseudoexon vary across cell types, impacting WT NEMO levels.
• SRSF6 protein binds to the pseudoexon, promoting its inclusion.
• Knockdown of SRSF6 or inhibition of CLK kinase restores WT NEMO expression and function.

Implications:

• A recurrent deep intronic splicing mutation in IKBKG causes a quantitative NEMO defect in males.
• The severity of the NEMO defect is cell-type dependent, being most pronounced in leukocytes.
• Targeting SRSF6 or CLK offers a potential therapeutic strategy for IKBKG-related disorders.