Novel DOCK8 gene mutations lead to absence of protein expression in patients with hyper-IgE syndrome
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ORIGINAL ARTICLE
Novel DOCK8 gene mutations lead to absence of protein expression in patients with hyper-IgE syndrome Tao Qin1 • Yunfei An2 • Chaohong Liu1 • Junfeng Wu2 • Rongxin Dai1 • Dawei Liu2 • Xiaohui Li1 • Liping Jiang1 • Daoqi Wu2 • Xuemei Tang2 • Wenxia Song3 • Tao Wang4 • Xiaodong Zhao1,2,5
Ó Springer Science+Business Media New York 2015
Abstract Autosomal recessive hyper-immunoglobulin E syndrome (AR-HIES) caused by DOCK8 defects is characterized by recurrent elevated serum IgE level, elevated peripheral eosinophil count, severe atopy, recurrent viral and bacterial infections, and early-onset malignancy. The clinical, genetic, and immunologic characteristics of DOCK8 mutations in Chinese patients have not been characterized in detail. In this research, we screened seven Chinese candidate patients for mutations within the DOCK8 gene and identified three large novel homozygous deletions and four novel point mutations by targeted deep sequencing. The homozygous deletions displayed autosomal recessive inheritance, and the point mutations were
sporadic. Absence of DOCK8 protein was confirmed using flow cytometry and western blotting. Besides the typical clinical features and immunologic impairments of DIDS, proliferation of lymphocytes, cytotoxic function of NK cells, and expression of IL-10 in regulatory B cells were severely impaired in DOCK8 mutant patients which may be associated with abnormal immune responses in DIDS. These findings will contribute to the early diagnosis and treatment of DOCK8 patients. Keywords Hyper-IgE syndrome DOCK8 Mutation Flow cytometry Targeted deep sequencing Immune function
& Tao Wang [email protected]
Introduction
& Xiaodong Zhao [email protected]
The hyper-IgE syndrome (HIES) is a collection of primary immunodeficiency syndrome that result in elevated serum IgE levels, recurrent staphylococcal skin abscesses, eczema, and pulmonary infections. The disorders have autosomal dominant and recessive forms. Autosomal recessive HIES (AR-HIES) is an immunodeficiency characterized by severe atopy, recurrent viral and bacterial infections, and early-onset malignancy. Unlike autosomal dominant (AD)-HIES, AR-HIES patients develop severe allergies to food and environmental antigens, including anaphylaxis and asthma. These clinical characteristics are accompanied by elevated serum IgE levels and high peripheral eosinophil counts [1, 2]. DOCK8 is a member of the DOCK180-related protein super family, a distinct class of guanine nucleotide exchange factors (GEFs) that modulate the activity of Rho GTPases [3]. DOCK8 deficiency, which is one of the primary causes of AR-HIES, was first described in 2004 [4], and mutations within the DOCK8
1
Research Center for Immunologic and Infectious diseases, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
2
Division of Immunology; Research Center for Immunologic and Infectious Diseases; Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical Univer
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