Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome

Abstract

Background Kabuki syndrome (KS) is a complex multi-system developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has previously been reported. Objective To characterize the humoral immune defects found in KS patients with KMT2D mutations. Methods We comprehensively characterize B cell function in a cohort (N = 13) of patients with KS (ages 4 months to 27 years). Results Three-quarters (77%) of the cohort had a detectable heterozygous KMT2D mutations (50% nonsense, 20% splice site, 30% missense), and 70% of the reported mutations are novel. Amongst the patients with KMT2D mutations (KMT2DMut/+), hypogammaglobulinemia was detected in all but one individual, with IgA deficiency affecting 90% of patients and a deficiency in at least one other isoform seen in 40% of patients. Total memory (CD27+) and class-switched memory B cells (IgM−) were significantly reduced in KMT2DMut/+ patients compared to controls (p-values < 0.001). KMT2DMut/+ patients also had significantly reduced rates of somatic hypermutation in IgG (p value = 0.003), but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in KMT2DMut/+ primary B cells. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains. Conclusions In patients with KS, autosomal dominant KMT2D mutations are associated with the dysregulation of terminal B cell differentiation leading to humoral immune deficiency and in some cases autoimmunity. All patients with KS should undergo serial clinical immune evaluations. Clinical Implications KMT2DMut/+ Kabuki syndrome causes IgA deficiency in nearly all patients, although additional humoral defects (memory B cell deficiency, IgG hypogammaglobulinemia) have variable expressivity. Missense mutations in terminal domains may increase autoimmunity risk.

An atypical case with chronic granulomatous disease and Kabuki syndrome

“…Instead, he might have benefitted from the concomitant CGD regarding the elevated Ig production. Additionally, KS causes reduced rates of somatic hypermutation of IgG and deficiency of IgA in nearly all patients due to the dysregulation in the B-cell terminal differentiation pathway (11). Our patient had increased IgA and IgG level and this was concordant with CGD.…”

“…Another question from this case is as follows: Did molecular upregulation due to KS play a role in the late presentation of CGD? KS is associated with a modest immunological defect in antibody formation, which may culminate in a common variable immunodeficiency like presentation (9,11). Many KS patients show increased susceptibility to infections and have reduced immunoglobulin serum levels due to the defect in the B-cell pathway (11), while some patients may suffer from autoimmune manifestations, such as autoimmune thyroiditis, idiopathic thrombocytopenia or hemolytic anemia (9,11).…”

A PTIP–PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex

“…7). Nevertheless, the CSR defects that we and others (Ortega-Molina et al 2015) observed with MLL3/MLL4 deficiencies in mice remain to be elucidated and may help to model the immune defects observed in human Kabuki syndrome that harbor mutations in Mll4 (Lindsley et al 2015).…”

Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management

“…Defects in histone and chromatin modification enzymes have been described in patients with Kabuki syndrome, a complex multisystem syndrome that includes hypogammaglobulinemia, reduced naïve and switched memory B cells, and an increase in the CD21 low B-cell population, all of which are often found in patients with CVID. In Kabuki syndrome, the B-cell differentiation defect was shown to be associated with an impaired histone modification process, which is fundamental for correct B-cell development [28].…”