28 January 2020
New mutation linked to hyper IgE syndrome
Published online 26 July 2019
A mutation, undetected by conventional screening, is implicated in a rare immunodeficiency disorder.
Geneticists and clinicians in France, Australia, Qatar and the US have uncovered a mutation underlying hyper IgE syndrome, a rare condition characterised by heightened vulnerability to skin and lung infections.
Many causal mutations of the syndrome have already been identified in the protein-coding regions of STAT3, a gene that plays an integral role in cell development. But around five per cent of familial cases remain unaccounted for genetically.
There is growing evidence that mutations in non-coding, or intronic, regions of genes are associated with inborn errors of immunity. This led the team to suspect that these less-studied regions of STAT3 might yield further clues.
The group, led by Jean-Laurent Casanova of Rockefeller University in New York, analysed DNA from three generations of a family in France, seven of whose members have hyper IgE syndrome.
They compared differences in nucleotide sequence that were so slight as to be overlooked by conventional analyses. They found that all seven patients, but not their healthy relatives, shared a deep intronic mutation in STAT3.
This mutation is responsible for generating an altered STAT3 protein named D427ins17. Even when this mutant protein is produced in small amounts, it appears to interfere with normal protein function through a mechanism called negative dominance.
Searching within the non-coding regions of STAT3 and other genes could reveal further mutations associated with unexplained cases of rare diseases.
Khourieh, J. et al. A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance. PNAS http://dx.doi.org/10.1073/pnas.1901409116 (2019).