Format

Send to

Choose Destination
J Allergy Clin Immunol. 2016 Jan;137(1):179-187.e10. doi: 10.1016/j.jaci.2015.06.002. Epub 2015 Jul 17.

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

Author information

1
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio. Electronic address: andrew.lindsley@cchmc.org.
2
Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
3
Division of Genetics, Stead Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
4
Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Bone Marrow Transplantation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
5
Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio.
6
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
7
Division of Pediatric Hematology/Oncology, University of North Carolina, Chapel Hill, NC.
8
Division of Immunology, Allergy and Rheumatology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Abstract

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.

KEYWORDS:

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

PMID:
26194542
PMCID:
PMC4715656
DOI:
10.1016/j.jaci.2015.06.002
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center