B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ

被引:92
作者
Salzer, Elisabeth [1 ]
Santos-Valente, Elisangela [1 ]
Klaver, Stefanie [1 ,2 ]
Ban, Sol A. [1 ]
Emminger, Wolfgang [3 ]
Prengemann, Nina Kathrin [1 ]
Garncarz, Wojciech [1 ]
Muellauer, Leonhard [4 ]
Kain, Renate [4 ]
Boztug, Heidrun [5 ,6 ]
Heitger, Andreas [5 ,6 ]
Arbeiter, Klaus [3 ]
Eitelberger, Franz
Seidel, Markus G. [5 ,6 ]
Holter, Wolfgang [5 ,6 ]
Pollak, Arnold [3 ]
Pickl, Winfried F. [7 ,8 ]
Foerster-Waldl, Elisabeth [3 ]
Boztug, Kaan [1 ,3 ]
机构
[1] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1010 Vienna, Austria
[2] Univ Sao Paulo, Inst Ciencias Biomed, BR-05508 Sao Paulo, Brazil
[3] Med Univ Vienna, Dept Pediat & Adolescent Med, A-1090 Vienna, Austria
[4] Med Univ Vienna, Clin Inst Pathol, A-1090 Vienna, Austria
[5] Med Univ Vienna, Dept Pediat, St Anna Kinderspital, A-1090 Vienna, Austria
[6] Med Univ Vienna, Childrens Canc Res Inst, A-1090 Vienna, Austria
[7] Med Univ Vienna, Christian Doppler Lab Immunomodulat, A-1090 Vienna, Austria
[8] Med Univ Vienna, Inst Immunol, Ctr Pathophysiol Infectiol & Immunol, A-1090 Vienna, Austria
基金
奥地利科学基金会;
关键词
MARCKS; GENE; IMMUNODEFICIENCY; POLYMORPHISM; DISEASE; PLCG2; CTLA4;
D O I
10.1182/blood-2012-10-460741
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Primary B-cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family suffering from recurrent infections and severe lupuslike autoimmunity. Immunophenotyping revealed progressive decrease of CD19(+) B cells, a defective class switch indicated by low numbers of IgM- nd IgG-memory B cells, as well as increased numbers of CD21(low) B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splicesite mutation in protein C kinase delta (PRKCD), causing the absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin (IL)-6 and IL-6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity.
引用
收藏
页码:3112 / 3116
页数:5
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