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A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.

Publication ,  Journal Article
Jabara, HH; Boyden, SE; Chou, J; Ramesh, N; Massaad, MJ; Benson, H; Bainter, W; Fraulino, D; Rahimov, F; Sieff, C; Liu, Z-J; Alshemmari, SH ...
Published in: Nature genetics
January 2016

Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

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Published In

Nature genetics

DOI

EISSN

1546-1718

ISSN

1061-4036

Publication Date

January 2016

Volume

48

Issue

1

Start / End Page

74 / 78

Related Subject Headings

  • Receptors, Transferrin
  • Pedigree
  • Oxidoreductases
  • Oncogene Proteins
  • Mutation, Missense
  • Mice, Mutant Strains
  • Mice, Inbred C57BL
  • Male
  • Immunologic Deficiency Syndromes
  • Humans
 

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Jabara, H. H., Boyden, S. E., Chou, J., Ramesh, N., Massaad, M. J., Benson, H., … Geha, R. S. (2016). A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nature Genetics, 48(1), 74–78. https://doi.org/10.1038/ng.3465
Jabara, Haifa H., Steven E. Boyden, Janet Chou, Narayanaswamy Ramesh, Michel J. Massaad, Halli Benson, Wayne Bainter, et al. “A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.Nature Genetics 48, no. 1 (January 2016): 74–78. https://doi.org/10.1038/ng.3465.
Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, et al. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nature genetics. 2016 Jan;48(1):74–8.
Jabara, Haifa H., et al. “A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.Nature Genetics, vol. 48, no. 1, Jan. 2016, pp. 74–78. Epmc, doi:10.1038/ng.3465.
Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, Bainter W, Fraulino D, Rahimov F, Sieff C, Liu Z-J, Alshemmari SH, Al-Ramadi BK, Al-Dhekri H, Arnaout R, Abu-Shukair M, Vatsayan A, Silver E, Ahuja S, Davies EG, Sola-Visner M, Ohsumi TK, Andrews NC, Notarangelo LD, Fleming MD, Al-Herz W, Kunkel LM, Geha RS. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nature genetics. 2016 Jan;48(1):74–78.

Published In

Nature genetics

DOI

EISSN

1546-1718

ISSN

1061-4036

Publication Date

January 2016

Volume

48

Issue

1

Start / End Page

74 / 78

Related Subject Headings

  • Receptors, Transferrin
  • Pedigree
  • Oxidoreductases
  • Oncogene Proteins
  • Mutation, Missense
  • Mice, Mutant Strains
  • Mice, Inbred C57BL
  • Male
  • Immunologic Deficiency Syndromes
  • Humans