Selective IgM immunodeficiency (sIgMID) represents a poorly understood dysgammaglobulinemia that is characterized by persistently low serum IgM levels (≤40mg/dl) and normal IgA and IgG levels. Patients with sIgMID often suffer from recurrent and/or severe infections, while less common manifestations include fibromyalgia, arthralgia, fatigue and autoimmune disorders. In a previous study we found altered B cell subsets, diminished IgM expression and profound defects in B-cell differentiation. To better understand disease pathology we aim to elucidate the genetic origin of sIgMID.
For our genetic analyses we apply whole-exome sequencing to search for sIgMID disease mutations which we follow-up and seek to validate experimentally, for example by gene editing.
So far, we identified 5 private missense variants in the gene Dedicator of Cytokinesis 11 (DOCK11) among 12 sIgMID patients. At least in one case the variant seems to affect activation of downstream proteins. In contrast, in a cohort of 100 CVID patients no private missense or nonsense DOCK11 variants were detected.
We found strong evidence that DOCK11 causes sIgMID. In our ongoing experiments we study the function of our DOCK11 candidate variants in B cells by applying CRISPR/Cas9-gene editing in LCLs to correct the variants back to wild type.