A novel mutation in the linker domain of the signal transducer and activator of transcription 3 gene, p.Lys531Glu, in hyper-IgE syndrome

Abstract

A novel mutation in the linker domain of the signal transducer and activator of transcription 3 gene, p.Lys531Glu, in hyper-IgE syndrome To the Editor:Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by eczema, recurrent abscesses, pneumonia with pneumatocele, and an increased serum IgE level. Most cases are sporadic, but both autosomal dominant and autosomal recessive forms have been described. 1 Recently, mutations in the signal transducer and activator of transcription factor 3 gene (STAT3) have been determined to be the cause of autosomal dominant HIES. 2,3 Most STAT3 mutations were located in the DNA-binding domain or Src homology 2 domain, whereas missense mutations were also found in the transactivation domain downstream of the Src homology 2 domain. [2][3][4] Here we report the first STAT3 mutation in the linker domain of the protein in a boy with HIES.A 5-year-old Korean boy was admitted because of fever, cough, and otorrhea for a week. His parents were not consanguineous. He had no remarkable perinatal problems and had been vaccinated as scheduled. He had a history of atopic dermatitis since 6 months of age. Ingestion of eggs and milk had been restricted until 43 months of age, when he passed the open challenge test. Of note, past medical history also revealed recurrent infections, including multiple episodes of oral candidiasis. He was treated with antibiotics for an abscess on the scalp caused by group A b-hemolytic Streptococcus species at 4 months of age. He had a history of 3 hospitalizations for pneumonia without pneumatocele. Suppurative cervical lymphadenitis caused by Staphylococcus aureus, which occurred at 18 months of age, was successfully treated with incision, drainage, and antibiotics, but it recurred several times afterward. At 4 years of age, tympanostomy tubes were inserted in the eardrums bilaterally for recurrent otitis media caused by Streptococcus pneumoniae. Family history revealed no members with relevant allergic or immunologic diseases.On physical examination, his height was 104.6 cm (10th percentile), and his weight was 17 kg (25th percentile). He had coarse facial features with a low hairline and hypertelorism and genu valgum. A whitish plaque was found on the soft palate. The left external auditory canal was wet, and the tympanostomy tube was not in situ in his left ear. A 1.0 3 1.0 cm, hard, tender lymph node was palpable in the left supraclavicular area. Fine crackles were heard on both lung fields, and his skin was slightly dry. Complete blood cell counts demonstrated a normal total eosinophil count (<400 cells/mL), although his eosinophil count had been up to 7000 cells/mL at 6 months of age. Plain chest radiographic analysis demonstrated bilateral peribronchial infiltrates, and Haemophilus influenzae was isolated from sputum culture. The serum IgE level was increased at 3980 IU/mL. Results of other immunologic studies, such as serum immunoglobulin level measurement and the nitroblue tetrazolium test, were normal. Lymphocyte subset ana...

Allosteric Communication across STAT3 Domains Associated with STAT3 Function and Disease-Causing Mutation

“…As discussed above, I568F is a HIES associated mutation in the LD 25; 26 . Coincidently, I568 undergoes the largest changes in structure and dynamics among all measured residues when the SH2 domain forms a complex with a pTyr-containing peptide (Figs.…”

“…Further investigation of the role of allostery in STAT function is needed, because currently available X-ray structures of STAT proteins do not provide sufficient understanding of the mechanisms underlying the conditions caused by some recently identified disease-inducing mutations 5 . Aberrantly weakened STAT3 signaling due to mutations are linked to various diseases including the hyper immunoglobulin E syndrome (HIES) 6; 7 .…”

Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome

“…We have confirmed that these mutations are located at mutation hotspots. [28,29,33,47,55,60,62,70,71] Exons 13, 16, and 21---in which these mutations are located---could thus be sequenced first, in cases of suspected STAT3 deficiency. An impairment of STAT3 phosphorylation and STAT3 translocation to the nucleus and DNA-binding were found in EBV-B cell lines from 9 patients bearing 5 previously identified heterozygous mutations (R382W, R382Q, T412S, Vdel463, and V637M) and from 7 patients bearing 6 previously unidentified heterozygous mutations (N472D, S614G, T708N, K709E, V713M, and T714I).…”

“…Since 2007, up to 230 STAT3-deficient patients have been reported in individual case reports [2–4,13, 33, 35, 41, 43, 44, 55, 61, 68, 71] or national or international series, including 8 patients (Japan), [47] 37 (United States and Europe), [60] 12 (Lebanon and Europe), [29] 50 (international), [28] 64 (international), [70] and 48 patients (international). [62] However, most reports have focused on the molecular and cellular defects of the patients, providing little clinical information.…”

Advances in basic and clinical immunology in 2009

“…22 Both microdeletions involving this gene and deleterious mutations in DOCK8 were found in 21 patients with AR-HIES, a syndrome characterized by recurrent pneumonia, skin abscesses and viral infections (especially molluscum contagiosum and herpes viruses), very high eosinophilia and elevated serum IgE level, but, in contrast to the autosomal dominant form, does not present with skeletal or dental disease. Kim and colleagues23 reported a missense mutation in the linker domain of the signal transducer and activator of transcription 3 (STAT3) in a patient with autosomal dominant HIES, expanding the range of genetic defects causing this syndrome, since previous reports had found mutations in either the DNA-binding domain transactivation domain or the SH2 domain. Of note, this 5 year-old boy did not have any skeletal or dental anomalies.…”