Researchers Identify Genetic Cause of Biblical Job’s Syndrome

Newswise — Researchers have discovered the genetic cause of a medical condition thought to be suffered by Job, a prominent biblical figure who was afflicted with painful sores from the soles of his feet to the top of his head.

"The genetic origins of this disease have been a mystery since it was first identified decades ago," said Dr. James M. Musser, co-director of The Methodist Hospital Research Institute and co-author of the findings published in the New England Journal of Medicine this week. "These results may lead to new diagnostic tests and new treatments to help patients afflicted with Job's Syndrome."

Job's Syndrome, or Hyper IgE Recurrent Infection Syndrome (HIES), is a rare disorder of the immune system and connective tissue, characterized by boils, inflamed, irritated skin, bone abnormalities, teeth deformities and cyst-forming pneumonias. It was first described in 1966 and fewer than 250 cases have been reported since that time.

"Although this is a rare disease, the novel strategies we developed can be applied to many other genetic diseases of unknown cause," Musser said.

The study, conducted at the National Institutes of Health (NIH), identified mutations in a gene that modulates the immune system, the signal transducer and activator of transcription 3 (STAT3), as the cause of this debilitating disease, a deficiency of the immune system. The research team sequenced the STAT3 gene and employed molecular and bioinformatics tools to decipher the genetic defect that leads to Job's Syndrome.

The growing field of bioinformatics capitalizes on the power of math and computers to make sense of the huge volume of data involved in molecular and genetic analysis. Future research on possible treatments for the disease can be targeted to this mutation.

For more information on The Methodist Hospital Research Institute, see http://www.methodistresearch.com.

Study Details

Methods: Longitudinal clinical data was collected from patients with HIES and their families, and assayed cytokines secreted by stimulated leukocytes and gene expression in resting and stimulated cells. These data implicated STAT3 as a candidate gene, which was then sequenced.

Results: Increased levels of pro-inflammatory gene transcripts were observed in unstimulated HIES patient peripheral blood neutrophils and mononuclear cells, compared with control cells. In vitro cultures of mononuclear cells from HIES patients stimulated with lipopolysaccharide (LPS) with or without interferon gamma had more tumor necrosis factor alpha than identically treated cells derived from unaffected persons (p=0.0028). In contrast, HIES patients' cells generated less monocyte chemoattractant protein-1 in response to interleukin-6 (p=0.031), suggesting a defect in IL-6 signaling through its downstream mediators, one of which is signal transducer and activator of transcription 3 (STAT3). The group identified missense mutations and single codon in-frame deletions in STAT3 in 48 familial and sporadic HIES cases. Eighteen discrete mutation sites, five of which were hotspots, were predicted to directly affect the DNA-binding and SH2 domains.

Conclusions: Mutations in STAT3 underlie sporadic and dominant HIES, an immunodeficiency with increased innate immune response, recurrent infections and complex somatic features.