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

Haifa H. Jabara; Steven E. Boyden; Janet Chou; Narayanaswamy Ramesh; Michel J. Massaad; Halli Benson; Wayne Bainter; David Fraulino; Fedik Rahimov; Colin Sieff; Zhi Jian Liu; Salem H. Alshemmari; Basel K. Al-Ramadi; Hasan Al-Dhekri; Rand Arnaout; Mohammad Abu-Shukair; Anant Vatsayan; Eli Silver; Sanjay Ahuja; E. Graham Davies; Martha Sola-Visner; Toshiro K. Ohsumi; Nancy C. Andrews; Luigi D. Notarangelo; Mark D. Fleming; Waleed Al-Herz; Louis M. Kunkel; Raif S. Geha

doi:10.1038/ng.3465

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

Haifa H. Jabara, Steven E. Boyden, Janet Chou, Narayanaswamy Ramesh, Michel J. Massaad, Halli Benson, Wayne Bainter, David Fraulino, Fedik Rahimov, Colin Sieff, Zhi Jian Liu, Salem H. Alshemmari, Basel K. Al-Ramadi, Hasan Al-Dhekri, Rand Arnaout, Mohammad Abu-Shukair, Anant Vatsayan, Eli Silver, Sanjay Ahuja, E. Graham DaviesMartha Sola-Visner, Toshiro K. Ohsumi, Nancy C. Andrews, Luigi D. Notarangelo, Mark D. Fleming, Waleed Al-Herz, Louis M. Kunkel, Raif S. Geha

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	74-78
Number of pages	5
Journal	Nature Genetics
Volume	48
Issue number	1
DOIs	https://doi.org/10.1038/ng.3465
Publication status	Published - Dec 29 2015

ASJC Scopus subject areas

Genetics

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Jabara, H. H., Boyden, S. E., Chou, J., Ramesh, N., Massaad, M. J., Benson, H., Bainter, W., Fraulino, D., Rahimov, F., Sieff, C., Liu, Z. J., Alshemmari, S. H., Al-Ramadi, B. K., Al-Dhekri, H., Arnaout, R., Abu-Shukair, M., Vatsayan, A., Silver, E., Ahuja, S., ... Geha, R. S. (2015). 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, HH, Boyden, SE, Chou, J, Ramesh, N, Massaad, MJ, Benson, H, Bainter, W, Fraulino, D, Rahimov, F, Sieff, C, Liu, ZJ, 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 2015, 'A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency', Nature Genetics, vol. 48, no. 1, pp. 74-78. https://doi.org/10.1038/ng.3465

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title = "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency",

abstract = "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.",

author = "Jabara, {Haifa H.} and Boyden, {Steven E.} and Janet Chou and Narayanaswamy Ramesh and Massaad, {Michel J.} and Halli Benson and Wayne Bainter and David Fraulino and Fedik Rahimov and Colin Sieff and Liu, {Zhi Jian} and Alshemmari, {Salem H.} and Al-Ramadi, {Basel K.} and Hasan Al-Dhekri and Rand Arnaout and Mohammad Abu-Shukair and Anant Vatsayan and Eli Silver and Sanjay Ahuja and Davies, {E. Graham} and Martha Sola-Visner and Ohsumi, {Toshiro K.} and Andrews, {Nancy C.} and Notarangelo, {Luigi D.} and Fleming, {Mark D.} and Waleed Al-Herz and Kunkel, {Louis M.} and Geha, {Raif S.}",

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doi = "10.1038/ng.3465",

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AU - Jabara, Haifa H.

AU - Boyden, Steven E.

AU - Chou, Janet

AU - Ramesh, Narayanaswamy

AU - Massaad, Michel J.

AU - Benson, Halli

AU - Bainter, Wayne

AU - Fraulino, David

AU - Rahimov, Fedik

AU - Sieff, Colin

AU - Liu, Zhi Jian

AU - Alshemmari, Salem H.

AU - Al-Ramadi, Basel K.

AU - Al-Dhekri, Hasan

AU - Arnaout, Rand

AU - Abu-Shukair, Mohammad

AU - Vatsayan, Anant

AU - Silver, Eli

AU - Ahuja, Sanjay

AU - Davies, E. Graham

AU - Sola-Visner, Martha

AU - Ohsumi, Toshiro K.

AU - Andrews, Nancy C.

AU - Notarangelo, Luigi D.

AU - Fleming, Mark D.

AU - Al-Herz, Waleed

AU - Kunkel, Louis M.

AU - Geha, Raif S.

PY - 2015/12/29

Y1 - 2015/12/29

N2 - 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.

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

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