ID
45078
Description
Principal Investigator: Michael J. Lenardo, MD, National Institute of Allergy and Infectious Dieases, National Institutes of Health, Bethesda, MD, USA MeSH: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000365 The etiologies of primary immunodeficiencies often yield novel insights about the immune system. Although a genetic etiology has been suspected for patients with abnormally low CD4+ T cells in the absence of HIV infection or any known causes of lymphopenia, no genetic mutation has been described to date for any case of primary CD4 lymphopenia. In this study, we characterized a non-consanguineous family with two non-HIV infected boys exhibiting an inverted CD4 to CD8 T cell ratio and a history of recurrent chronic viral infections since birth. Consistent with a decreased thymic output of CD4+ T cells, the percentage of CD31+ cells in the CD4+ naive population of these patients was decreased. In addition, the activation of T cells was significantly impaired in the patient upon TCR stimulation. Given the mother's T cells show completely skewed X chromosome inactivation, we suspected that the nature of this disease is X-linked. We performed X-chromosome exon-capture targeted single-end Solexa sequencing on two brothers and the mother and found a 10 base pair deletion at an intron-exon junction of Magnesium Transporter 1 (MAGT1), a Mgsup2+/sup specific transporter. We confirmed that this deletion leads to altered splicing, frameshift, early termination of the mRNA, and deficient protein expression in the lymphocytes of the two patients. Moreover, knockdown of this transporter in T cells isolated from healthy donors can recapitulate the observed T cell activation defect while its ectopic expression in the patients' lymphocytes can restore T cell stimulation. Our discovery highlights the significance of this transporter to T cell function.
Link
https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000365
Keywords
Versions (2)
- 8/19/22 8/19/22 - Simon Heim
- 10/12/22 10/12/22 - Adrian Schulz
Copyright Holder
Michael J. Lenardo, MD, National Institute of Allergy and Infectious Dieases, National Institutes of Health, Bethesda, MD, USA
Uploaded on
August 19, 2022
DOI
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License
Creative Commons BY 4.0
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dbGaP phs000365 Genetic Basis of XMEN Disease
This data table contains subject IDs and consent group information. The data table also includes a mapping of subject IDs to other subject ID aliases.
- StudyEvent: SEV1
- This data table contains subject IDs and consent group information. The data table also includes a mapping of subject IDs to other subject ID aliases.
- The data table contains subject pedigree information.
- The data table contains a mapping of subject ID to sample ID. Samples are the final preps submitted for sequencing. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. The data table also includes a mapping of sample IDs to other sample ID aliases.
- This subject phenotype table includes subject age, birthplace, sex, race, inverted CD4:CD8 T cell ratio, ability to clear EBV infection, and mutation in MAGT1.
- This sample attributes table includes variables indicating the body site where the sample was extracted, sample analyte type, and sample histological type.
Similar models
This data table contains subject IDs and consent group information. The data table also includes a mapping of subject IDs to other subject ID aliases.
- StudyEvent: SEV1
- This data table contains subject IDs and consent group information. The data table also includes a mapping of subject IDs to other subject ID aliases.
- The data table contains subject pedigree information.
- The data table contains a mapping of subject ID to sample ID. Samples are the final preps submitted for sequencing. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. The data table also includes a mapping of sample IDs to other sample ID aliases.
- This subject phenotype table includes subject age, birthplace, sex, race, inverted CD4:CD8 T cell ratio, ability to clear EBV infection, and mutation in MAGT1.
- This sample attributes table includes variables indicating the body site where the sample was extracted, sample analyte type, and sample histological type.
C1257890 (UMLS CUI [1,2])
C3847505 (UMLS CUI [1,2])
C0449416 (UMLS CUI [1,2])
C3847505 (UMLS CUI [1,3])