Recent Advances in DOCK8 Immunodeficiency Syndrome

Zhang, Qian; Jing, Huie; Su, Helen C.

doi:10.1007/s10875-016-0296-z

Cited by 34 publications

(46 citation statements)

References 58 publications

(100 reference statements)

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“…We review here the history of HIES, and what is currently known about its three proposed genetic forms, and we discuss the contribution of the corresponding mouse models to studies of the pathogenesis of this disease. Like other investigators [14, 15], we suggest that the term “HIES” best applies to patients with a phenotype of AD STAT3 deficiency.…”

Section: Introductionsupporting

confidence: 51%

“…Most patients present with severe allergy, chronic infections, and early-onset cancer. The clinical presentation and treatment of this condition were recently extensively reviewed; about 200 patients have been reported worldwide [15, 136, 137]. The first sign suggestive of DOCK8 deficiency is usually severe allergies, including atopic dermatitis soon after birth, asthma, multiple food and respiratory allergies.…”

Section: Dock8 Deficiencymentioning

confidence: 99%

“…More than half the patients have been reported to have life-threatening infections, with overall survival was as low as 37% at 30 years of age [136]. It is, therefore, unsurprising that DOCK8 deficiency is increasingly considered to be a CID rather than a form of HIES, as proposed by Helen Su in her seminal paper [5, 15]. The immunological phenotypes of DOCK8 deficiency include high serum IgE levels, eosinophilia, and T- and NK-cell lymphopenia.…”

Section: Dock8 Deficiencymentioning

confidence: 99%

“…The first is the high frequency of large deletions (CNVs), which have been identified in more than half the patients. The mechanism for the unusually high frequency of deletions probably involves frequent homologous recombination between repetitive DNA sequence elements over a large stretch of the DOCK8 locus close to the telomere [15]. This high frequency of homologous recombination also accounts for the other specific feature of DOCK8 deficiency, including its unusually high frequency of somatic reversion.…”

Section: Dock8 Deficiencymentioning

confidence: 99%

“…However, many other inborn errors of immunity leading to high serum IgE levels and severe infections, including Wiskott-Aldrich syndrome ( WAS or WIPF1 mutations), DiGeorge Syndrome (22q11.2DS), Omenn Syndrome (hypomorphic mutations in genes for which null alleles underlie SCID), immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX, FOXP3 mutations), and Netherton/Comèl-Netherton syndrome ( SPINK5 mutations), have never been considered to belong to the HIES group. AD STAT3, AR DOCK8, and AR PGM3 deficiencies are currently considered to be bona fide forms of HIES by some investigators [6, 10-12], but not others [5, 11, 13-15]. Only Job’s syndrome and PGM3 deficiency are recognized as HIES in the International Union of Immunological Societies 2018 classification, which considers DOCK8 deficiency to be a combined immunodeficiency (CID) [11].…”

Section: Introductionmentioning

confidence: 99%

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Human hyper-IgE syndrome: singular or plural?

et al. 2018

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Spectacular progress has been made in the characterization of human hyper-IgE syndrome (HIES) over the last 50 years. HIES is a primary immunodeficiency defined as an association of atopy in a context of very high serum IgE levels, characteristic bacterial and fungal diseases, low-level clinical and biological inflammation, and various non-hematopoietic developmental manifestations. Somewhat arbitrarily, three disorders were successively put forward as the underlying cause of HIES: autosomal dominant (AD) STAT3 deficiency, the only disorder corresponding to the original definition of HIES, and autosomal recessive (AR) DOCK8 and PGM3 deficiencies, in which atopy and high serum IgE levels occur in a context of manifestations not seen in patients with typical HIES. Indeed, these three disorders disrupt different molecular pathways, affect different cell types, and underlie different clinical phenotypes. Surprisingly, several other inherited inborn errors of immunity in which serum IgE levels are high, sometimes almost as high as those in HIES patients, are not considered to belong to the HIES group of diseases. Studies of HIES have been further complicated by the lack of a high serum IgE phenotype in all mouse models of the disease other than two Stat3 mutant strains. The study of infections in mutant mice has helped elucidate only some forms of HIES and infection. Mouse models of these conditions have also been used to study non-hematopoietic phenotypes for STAT3 deficiency, tissue-specific immunity for DOCK8 deficiency, and cell lineage maturation for PGM3 deficiency. We review here the history of the field of HIES since the first clinical description of this condition in 1966, together with the three disorders commonly referred to as HIES, focusing, in particular, on their mouse models. We propose the restriction of the term "HIES" to patients with an AD STAT3-deficiency phenotype, including the most recently described AR ZNF341 deficiency, thus excluding AR DOCK8 and PGM3 deficiencies from the definition of this disease.

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Section: Introductionsupporting

confidence: 51%

Section: Dock8 Deficiencymentioning

confidence: 99%

Section: Dock8 Deficiencymentioning

confidence: 99%

Section: Dock8 Deficiencymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human hyper-IgE syndrome: singular or plural?

et al. 2018

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DOCK3‐related neurodevelopmental syndrome: Biallelic intragenic deletion of DOCK3 in a boy with developmental delay and hypotonia

Iwata‐Otsubo

Ritter

Weckselbatt

et al. 2017

American J of Med Genetics Pt A

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Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6–12 of the DOCK3 gene at 3p21.2. Symptoms of our proband resembles a phenotype of Dock3 knockout mice exhibiting sensorimotor impairments. Furthermore, our proband has clinical similarities with two siblings with compound heterozygous loss‐of‐function mutations of DOCK3 reported in [Helbig, Mroske, Moorthy, Sajan, and Velinov (); https://doi.org/10.1111/cge.12995]. Biallelic DOCK3 mutations cause a neurodevelopmental disorder characterized by unsteady gait, hypotonia, and developmental delay.

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Development of Impedimetric Immunosensors for the Diagnosis of DOCK8 and STAT3 Related Hyper‐Immunoglobulin E Syndrome

et al. 2018

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Hyper Immunoglobulin E syndrome (HIES) is a rare inherited inborn error of primary immunodeficiency. HIES is characterized by high levels of serum immunoglobulin E (IgE), severe eczema, which overlap with atopic dermatitis, as well as lung infections and even death. HIESs are genetically inherited by heterozygous or homozygous mutations in signal transducer and activator of transcription 3 (STAT3) or Dedicator of cytokinesis 8 (DOCK8) genes, in autosomal dominant and recessive forms, respectively. Therefore, the early detection of DOCK8 and STAT3 protein levels in humans would facilitate the early diagnosis of these disorders and thus, help in the disease management. Here, we present the development of immunosensors for the detection of DOCK8 and STAT3 using electrochemical impedance spectroscopy in a label‐free format. The immunosensors were fabricated by the covalent attachment of specific antibodies for DOCK8 and STAT3 on gold electrodes via cysteamine/phenylene diisothiocyanate linkers. The detection was achieved by monitoring the change in the charge transfer resistance (Rct) of ferro/ferricyanide redox couple upon binding of the proteins to the immunosensor surface. These biosensors enabled the detection of DOCK8 and STAT3 levels with low detection limits of 1.2 and 9.0 pg/ml, respectively. The immunosensor was also applied for the detection of DOCK8 in human serum samples showing high recovery percentages which indicates great promise of this method for early diagnosis of HIES in newborn infants.

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Recent Advances in DOCK8 Immunodeficiency Syndrome

Cited by 34 publications

References 58 publications

Human hyper-IgE syndrome: singular or plural?

Human hyper-IgE syndrome: singular or plural?

DOCK3‐related neurodevelopmental syndrome: Biallelic intragenic deletion of DOCK3 in a boy with developmental delay and hypotonia

Development of Impedimetric Immunosensors for the Diagnosis of DOCK8 and STAT3 Related Hyper‐Immunoglobulin E Syndrome

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