Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome
(1, 2, 3)
,
(4, 5, 6)
,
(7, 8)
,
(9, 10)
,
(2, 3)
,
(7, 8)
,
(5)
,
(7, 8)
,
(4, 6)
,
(9, 10)
,
(4, 6)
,
(7, 8)
,
(11)
,
(6, 4)
,
(12, 13)
,
(13, 12)
,
(14)
,
(3, 2)
,
(2, 3)
,
(3, 2)
,
(3, 2)
,
(3, 2)
,
(3, 2)
,
(15)
,
(3, 2, 1)
,
(4)
,
(16)
,
(16)
,
(16)
,
(16)
,
(5, 4)
,
(17)
,
(16)
,
(18)
,
(19)
,
(19)
,
(20)
,
(21)
,
(22)
,
(23)
,
(22)
,
,
(24)
,
(19)
,
(5)
,
(3, 2, 1)
,
(25, 26)
,
(27, 28, 29)
,
(30, 31, 24)
,
(32)
,
(25)
,
(24)
,
(33, 34)
,
(13, 35)
,
(9, 36)
,
(7, 8)
,
(4)
,
(3, 2, 1, 37)
,
(3, 2, 1)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Simon Tavernier
- Function : Author
- PersonId : 795643
- ORCID : 0000-0003-2514-5655
Cindy Ma
- Function : Author
- PersonId : 794453
- ORCID : 0000-0001-5387-8413
Marie Materna
- Function : Author
- PersonId : 800325
- ORCID : 0000-0003-1180-6651
Kathleen Claes
- Function : Author
- PersonId : 791343
- ORCID : 0000-0003-0841-7372
Louis-Marie Charbonnier
- Function : Author
- PersonId : 765174
- ORCID : 0000-0002-4594-7893
Sevgi Keles
- Function : Author
- PersonId : 779159
- ORCID : 0000-0001-7344-8947
Majistor Raj Luxman Maglorius Renkilaraj
- Function : Author
- PersonId : 782741
- ORCID : 0000-0002-8385-2860
Yoann Seeleuthner
- Function : Author
- PersonId : 779912
- ORCID : 0000-0002-1878-8567
Mélanie Migaud
- Function : Author
- PersonId : 769678
- ORCID : 0000-0003-3062-1214
Bertrand Boisson
- Function : Author
- PersonId : 757762
- ORCID : 0000-0001-5240-3555
- IdRef : 08188317X
Véronique Avettand-Fenoël
- Function : Author
- PersonId : 765802
- ORCID : 0000-0002-7022-2990
- IdRef : 09320955X
Sule Haskologlu
- Function : Author
- PersonId : 800326
- ORCID : 0000-0002-2668-0441
Figen Dogu
- Function : Author
- PersonId : 779161
- ORCID : 0000-0002-7869-4941
Clément Gauvain
- Function : Author
Aydan Ikinciogullari
- Function : Author
- PersonId : 779160
- ORCID : 0000-0003-1145-0843
Rudi Beyaert
- Function : Author
- PersonId : 883571
Laurent Abel
- Function : Author
- PersonId : 756191
- ORCID : 0000-0001-7016-6493
- IdRef : 07779432X
Joshua Milner
- Function : Author
- PersonId : 800327
- ORCID : 0000-0002-3913-3869
Jean-Laurent Casanova
- Function : Author
- PersonId : 756193
- ORCID : 0000-0002-7782-4169
- IdRef : 073388726
Anne Puel
- Function : Author
- PersonId : 757898
- ORCID : 0000-0003-2603-0323
- IdRef : 170297969
Abstract
Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.