A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance
2019
Heterozygous in-frame mutations in
coding regionsof human
STAT3underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The
mutant proteinsare loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of
mutant proteinshas not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous
STAT3mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the
STAT3
complementary DNA, which, when overexpressed, generates a mutant
STAT3protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type
STAT3, on mass spectrometry. The patients’ primary B and T lymphocytes responded poorly to
STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical
STAT3coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing
STAT3introns in patients with HIES without candidate variants in
coding regionsand essential splice sites. They also show that AD HIES-causing
STAT3mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type
STAT3.
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