03 February 2023
Gene mutation implicated in rare immunodeficiency
Published online 10 December 2015
For the first time, a gene mutation that implicates impaired iron transport in the pathogenesis of an immunodeficiency has been identified.
An international research team sequenced genomes of children from two families in Kuwait and Saudi Arabia affected by a genetically undiagnosed form of combined immunodeficiency (CID), a serious disease in which combined deficiency of T and B lymphocytes can lead to life-threatening infections1.
CID is very common in Kuwait, with 1 in 7,500 people living with the disease, says immunologist Raif Geha from Harvard Medical School.
Although many genetic defects have been implicated in CID, many patients remain without a genetic diagnosis.
But this team identified, in a first, a mutation in a gene coding for transferrin receptor 1 protein (TfR1), important for the internalization of iron in blood cells, as a cause of CID. Iron is important for the development, proliferation and differentiation of blood cells.
“The surprising finding was that red cell development, which is known to be dependent on TfR1, was relatively well preserved,” says Geha.
“This has led to the discovery that an accessory protein, called STEAP3, which is expressed in red blood cell precursors, can associate with TfR1 and compensate for the internalization defect caused by the mutation.”
STEAP3 could be a potential approach for gene therapy in these patients, adds Gefa.
The discovery should allow early diagnosis of the condition so clinicians can rapidly conduct a stem cell transplant, which resolves it. It will also allow genetic counselling and pre-implantation diagnosis in couples who are heterozygous carriers of the mutation.
The team included researchers from Kuwait University, King Faisal Specialist Hospital and Research Center in Saudi Arabia, Queen Rania Hospital for Children in Jordan, and the College of Medicine and Health Sciences in the United Arab Emirates.
- Jabara, H. H. et al. A missense mutation in TFRC, encoding transferring receptor 1, causes combined immunodeficiency. Nat. Genet. http://dx.doi.org/10.1038/ng.3465 (2015).