LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency

被引:196
作者
Alangari, Abdullah [1 ]
Alsultan, Abdulrahman [1 ]
Adly, Nouran
Massaad, Michel J. [3 ]
Kiani, Iram Shakir [2 ]
Aljebreen, Abdulrahman [2 ]
Raddaoui, Emad [3 ]
Almomen, Abdul-Kareem [2 ]
Al-Muhsen, Saleh [1 ]
Geha, Raif S. [5 ,6 ]
Alkuraya, Fowzan S. [1 ,4 ,7 ]
机构
[1] King Saud Univ, Dept Pediat, King Khalid Univ Hosp, Riyadh, Saudi Arabia
[2] King Saud Univ, Dept Internal Med, King Khalid Univ Hosp, Riyadh, Saudi Arabia
[3] King Saud Univ, Dept Pathol, King Khalid Univ Hosp, Riyadh, Saudi Arabia
[4] King Faisal Specialist Hosp & Res Ctr, Dev Genet Unit, Dept Genet, Riyadh 11211, Saudi Arabia
[5] Harvard Univ, Sch Med, Boston, MA USA
[6] Childrens Hosp, Div Immunol, Boston, MA 02115 USA
[7] Alfaisal Univ, Coll Med, Dept Anat & Cell Biol, Riyadh, Saudi Arabia
基金
美国国家卫生研究院;
关键词
LPS-responsive beige-like anchor (LRBA); chronic diarrhea; common variable immunodeficiency; autoimmunity; COMMON VARIABLE IMMUNODEFICIENCY; ANTIBODY-DEFICIENCY SYNDROME; B-CELL; TACI;
D O I
10.1016/j.jaci.2012.05.043
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: Clinical immunology has traditionally relied on accurate phenotyping of the patient's immune dysfunction for the identification of a candidate gene or genes for sequencing and molecular confirmation. Although this is also true for other branches of medicine, the marked variability in immune-related phenotypes and the highly complex network of molecules that confer normal host immunity are challenges that clinical immunologists often face in their quest to establish a specific genetic diagnosis. Objective: We sought to identify the underlying genetic cause in a consanguineous family with chronic inflammatory bowel disease-like disorder and combined immunodeficiency. Methods: We performed exome sequencing followed by autozygome filtration. Results: A truncating mutation in LPS-responsive beige-like anchor (LRBA), which abolished protein expression, was identified as the most likely candidate variant in this family. Conclusion: The combined exome sequencing and autozygosity mapping approach is a powerful tool in the study of atypical immune dysfunctions. We identify LRBA as a novel immunodeficiency candidate gene the precise role of which in the immune system requires future studies. (J Allergy Clin Immunol 2012; 130:481-8.)
引用
收藏
页码:481 / +
页数:10
相关论文
共 30 条
[1]   Characterization of Immunologic Defects in Patients with Common Variable Immunodeficiency (CVID) with Intestinal Disease [J].
Agarwal, Shradha ;
Smereka, Paul ;
Harpaz, Noam ;
Cunningham-Rundles, Charlotte ;
Mayer, Lloyd .
INFLAMMATORY BOWEL DISEASES, 2011, 17 (01) :251-259
[2]  
Al-Herz W, 2011, FRONT PRIMARY IMMUNO, V2, P1
[3]   Autozygome decoded [J].
Alkuraya, Fowzan S. .
GENETICS IN MEDICINE, 2010, 12 (12) :765-771
[4]   Exome sequencing as a tool for Mendelian disease gene discovery [J].
Bamshad, Michael J. ;
Ng, Sarah B. ;
Bigham, Abigail W. ;
Tabor, Holly K. ;
Emond, Mary J. ;
Nickerson, Deborah A. ;
Shendure, Jay .
NATURE REVIEWS GENETICS, 2011, 12 (11) :745-755
[5]   Interactive visual analysis of SNP data for rapid autozygosity mapping in consanguineous families [J].
Carr, Ian M. ;
Flintoff, Kimberley J. ;
Taylor, Graham R. ;
Markham, Alexander F. ;
Bonthron, David T. .
HUMAN MUTATION, 2006, 27 (10) :1041-1046
[6]   TACI is mutant in common variable immunodeficiency and IgA deficiency [J].
Castigli, E ;
Wilson, SA ;
Garibyan, L ;
Rachid, R ;
Bonilla, F ;
Schneider, L ;
Geha, RS .
NATURE GENETICS, 2005, 37 (08) :829-834
[7]  
Cunningham-Rundles C, IMMUNOL RES
[8]   SEL-2, the C-elegans neurobeachin/LRBA homolog, is a negative regulator of lin-12/Notch activity and affects endosomal traffic in polarized epithelial cells [J].
de Souza, Natalie ;
Vallier, Laura G. ;
Fares, Hanna ;
Greenwald, Iva .
DEVELOPMENT, 2007, 134 (04) :691-702
[9]   Human primary immunodeficiency diseases [J].
Fischer, Alain .
IMMUNITY, 2007, 27 (06) :835-845
[10]   A DEFECT IN THE EARLY PHASE OF T-CELL RECEPTOR-MEDIATED T-CELL ACTIVATION IN PATIENTS WITH COMMON VARIABLE IMMUNODEFICIENCY [J].
FISCHER, MB ;
HAUBER, I ;
EGGENBAUER, H ;
THON, V ;
VOGEL, E ;
SCHAFFER, E ;
LOKAJ, J ;
LITZMAN, J ;
WOLF, HM ;
MANNHALTER, JW ;
EIBL, MM .
BLOOD, 1994, 84 (12) :4234-4241