Mutant protein variant explains dominant inheritance of genetic immunodeficiency

New research shows how a mutant form of a protein named STAT3 causes a genetically dominant immunodeficiency. "Accordingly, this study provides vital insight into a signaling pathway essential in human biology," Joseph Mackie and colleagues write. Some inherited conditions are autosomal recessive, meaning that they result from the inheritance of two disease-causing gene variants – one from each parent.

Autosomal dominant diseases, on the other hand, arise from a single copy of a disease-causing gene variant, which has effects that persist even after inheriting the other normal copy of the gene. For example, in the autosomal dominant form of hyper-IgE syndrome (HIES), the inheritance of a variant form of the gene STAT3 causes immunodeficiency even though patients also have one normal copy of the gene. STAT3 is a transcription factor that is important for immunity because it drives the expression of genes in response to many of the cytokines that determine how immune cells function.

Upon cytokine stimulation, STAT3 activates and forms structures called dimers with other STAT3 molecules, which move into the nucleus to regulate gene expression. Mackie et al. identified a patient harboring a unique STAT3 variant (STAT3^R31Q) that had not been documented previously in patients with HIES. Compared with the normal form of the protein, STAT3^R31Q was less able to drive the expression of target genes when the researchers stimulated immune cells with cytokines.

Furthermore, STAT3^R31Q preferentially formed dimers with the normal form of STAT3, and these STAT3: STAT3^R31Q heterodimers remained in the cytoplasm instead of moving into the nucleus. This combination of impaired gene expression regulation and the formation of dimers with normal STAT3 explains why a single copy of the STAT3^R31Q allele causes HIES, Mackie et al. say.