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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:137

Article

Lindsley, Andrew W.^1,4  Saal, Howard M.^2,4  Burrow, Thomas A.^2,4  Hopkin, Robert J.^2,4  Shchelochkov, Oleg⁶  Khandelwal, Pooja^3,4  Xie, Changchun⁵  Bleesing, Jack^3,4  Filipovich, Lisa^3,4  Risma, Kimberly^1,4  Assa'ad, Amal H.^1,4  Roehrs, Phillip A.⁷  Bernstein, Jonathan A.⁸ 

[1] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA

[2] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA

[3] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat, Cincinnati, OH 45229 USA

[4] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA

[5] Univ Cincinnati, Div Biostatist & Bioinformat, Dept Environm Hlth, Cincinnati, OH 45221 USA

[6] Univ Iowa Hosp & Clin, Dept Pediat, Div Genet, Iowa City, IA 52242 USA

[7] Univ N Carolina, Div Pediat Hematol Oncol, Chapel Hill, NC USA

[8] Univ Cincinnati, Div Immunol Allergy & Rheumatol, Dept Internal Med, Coll Med, Cincinnati, OH 45221 USA

关键词: Kabuki syndrome;    KMT2D;    KDM6A;    hypogammaglobulinemia;    memory B cells;    CD21(lo) B cells;    class-switch recombination;    somatic hypermutation;    PTIP;    AICDA;    AID;    polymerase eta;   

DOI  :  10.1016/j.jaci.2015.06.002

来源: Elsevier

【 摘 要 】

Background: Kabuki syndrome (KS) is a complex multisystem 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 been reported. Objective: We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. Methods: We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). Results: Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27(+)) and class-switched memory B cells (IgM(-)) were significantly reduced in patients with KMT2D(Mut/+) mutations compared with numbers in control subjects (P < .001). Patients with KMT2D(Mut/+) mutations also had significantly reduced rates of somatic hypermutation in IgG (P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations. 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 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.

【 授权许可】

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