A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

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Significance Heterozygous in-frame mutations in human STAT3 coding regions underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon, encoding a new mRNA (D427ins17) and a mutant loss-of-function, dominant-negative STAT3 protein. This mutant protein was not detected in heterozygous cells from the patient. We show that the D427ins17 mutant allele is dominant-negative despite the production of significantly smaller amounts of mutant than of wild-type protein in heterozygous cells. These findings highlight the importance of searching for deep intronic mutations in STAT3 before considering alternative genetic etiologies of HIES.

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