Autosomal dominant hyper-IgE syndrome – STAT3  and ZNF341 gene.


Autosomal dominant hyper IgE syndrome (AD-HIES), also known as Job syndrome or STAT3 deficient hyper IgE syndrome, is a process that affects several organism systems, particularly the immune system. Recurrent infections are common in people with AD-HIES. Affected individuals suffer frequent episodes of pneumonia, skin infections and eczema. Skin problems include rashes, blisters, abscesses and ulcers. Job´s syndrome, or AD-HIES, is characterized by abnormally high concentrations of immunoglobulin E (IgE) in the blood. IgE triggers an immune response against invaders in the body, especially parasitic helminths, and plays a role in allergies. It is not clear why these individuals have such high concentrations of IgE.

Autosomal dominant hyper IgE syndrome also affects other parts of the body, including bones and teeth. Many people have skeletal abnormalities such as hyperextensibility, scoliosis, osteopenia and a tendency for bones to fracture easily. In addition, dental anomalies are also characteristic of this disease. For example, primary teeth do not fall at the usual time in childhood. Other signs and symptoms may include coronary artery abnormalities, characteristic facial features and structural abnormalities of the brain, which generally do not affect intelligence.

Most cases of AD-HIES are due to mutations in the STAT3 (signal transducer and activator of transcription 3) gene, located on the long arm of chromosome 17 (17q21.31). This gene encodes the STAT3 protein, involved in many cellular functions. This protein regulates the genes that are involved in cell growth, division and movement, as well as in apoptosis; It plays an important role in the development and function of various organism systems: in the immune system, the protein transmits signals that help control the body´s response to invaders such as bacteria and fungi; In addition, the STAT3 protein is involved in the regulation of inflammation. In the skeletal system, the STAT3 protein is involved in the formation of specialized cells that constitute and break down bone tissue. These cells are necessary for normal development and maintenance of bones.

More than 100 germline mutations in the STAT3 gene have been recorded in people with autosomal dominant hyper IgE syndrome (AD-HIES). Most of the mutations involved consist of amino acid changes in the STAT3 protein. These mutations occur in regions of the protein that are critical for their activation or their ability to bind to DNA. The changes in the STAT3 gene responsible for the development of AD-HIES alter the structure and function of the STAT3 protein, affecting its ability to control the activity of other genes. These loss of function mutations alter the normal maturation of T cells, specifically a subset known as Th17 cells, and other cells of the immune system. As a consequence, people with AD-HIES are highly susceptible to infections, particularly bacterial and fungal infections that affect the lungs and skin. In addition, the role of the STAT3 protein in the formation and maintenance of bone tissue can help explain why mutations of the STAT3 gene result in the skeletal and dental abnormalities characteristic of this condition. When AD-HIES is not due to mutations in the STAT3 gene, the genetic cause of the disease is unknown.

Mutations in the ZNF341 gene (zinc finger protein 341), located on the long arm of chromosome 20 (20q11.22), lead to the development of a process similar to AD-HIES but with a different inheritance pattern. The ZNF341 gene encodes a transcription factor that regulates the activity of the STAT1 and STAT3 genes, controlling the production of the STAT1 and STAT3 proteins, respectively. Both proteins are involved in the immune system. It is believed that the ZNF341 protein controls the activity of other genes, although they have not been identified.

At least five mutations in the ZNF341 gene involved in the development of a process similar to AD-HIES have been identified. The mutations described result in the synthesis of an abnormally short ZNF341 protein or inhibit protein synthesis. With little or no ZNF341 protein, the production of STAT1 and STAT3 proteins is affected. Functional STAT3 deficiency blocks the maturation of T cells (specifically a subset known as Th17 cells) and other immune cells.

Autosomal dominant hyper IgE syndrome (AD-HIES) is inherited with an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the process. In about 50% of all cases due to mutations in the STAT3 gene, an affected person inherits the genetic change from an affected parent. Other cases are due to new mutations in this gene and occur in people with no history of the disease in their family. Mutations in the ZNF341 gene are inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we performed the detection of mutations associated with autosomal dominant hyper IgE syndrome (AD-HIES), by complete PCR amplification of the exons of the STAT3 and ZNF341 genes, respectively, and their subsequent sequencing.

Recommended samples: blood taken with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).