A number sign (#) is used with this entry because of evidence that immunodeficiency-46 (IMD46) is caused by homozygous mutation in the TFRC gene (190010) on chromosome 3q29.

Jabara et al. (2016) reported a large, highly consanguineous Kuwaiti kindred in which 14 children had a primary immunodeficiency resulting in severe childhood infections. A 5-year-old boy from western Saudi Arabia, born of consanguineous parents, had a similar disorder characterized by early-onset chronic diarrhea and recurrent infections. Laboratory studies from available patients showed hypo- or agammaglobulinemia, normal lymphocyte counts, intermittent neutropenia, and intermittent thrombocytopenia. Additional findings included mild anemia resistant to iron supplementation and low mean corpuscular volume (MCV). Although absolute numbers of circulating immune cells were normal, patients had decreased numbers of memory B cells, impaired immunoglobulin class-switching, and decreased proliferative responses of T cells. Six patients died; 8 received hematopoietic stem cell transplantation with resolution of the phenotype.

The transmission pattern of IMD46 in the families reported by Jabara et al. (2016) was consistent with autosomal recessive inheritance.

In affected members of a large consanguineous Kuwaiti family with IMD46, Jabara et al. (2016) identified a homozygous missense mutation in the TFRC gene (Y20H; 190010.0001). The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. An unrelated patient with a similar disorder carried the same homozygous mutation. Patient lymphocytes showed increased surface expression of TFRC (up to 13-fold higher than controls) and impaired TFRC internalization. Transduction of patient cells with wildtype TFRC corrected cell surface expression and corrected B- and T-cell function in vitro. Addition of iron citrate also corrected the lymphocyte proliferation defect in vitro, suggesting that insufficient iron uptake is the cause of defective B- and T-cell activation in affected individuals. Patient erythrocyte precursors showed lesser increases in TFRC membrane expression (up to 2.5-fold higher than controls) than the lymphocytes, suggesting that erythrocytes have a compensatory mechanism for TFRC internalization, which could also explain the mild anemia. STEAP3 (609671), which is expressed in erythroblasts and associated with TFRC, partially rescued the transferrin uptake defect in patient-derived fibroblasts. The overall findings demonstrated the importance of TFRC in adaptive immunity.

Jabara et al. (2016) found that transgenic mice homozygous for the human TFRC mutation Y20H were viable, indicating that the mutation resulted in a hypomorphic allele. Mutant mice had decreased serum IgG, hemoglobin, and MCV compared to controls, but normal percentages of splenic T and B cells, naive and memory T cells, and NK cells. However, mutant T cells showed impaired proliferative responses, which was improved by the addition of iron citrate, and B cells showed impaired immunoglobulin secretion in response to stimulation. TFRC surface expression on mutant T and B cells was significantly increased, reflecting impaired internalization.