University of Oulu

Keskitalo, S., Haapaniemi, E. M., Glumoff, V., Liu, X., Lehtinen, V., Fogarty, C., … Varjosalo, M. (2019). Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease. Npj Genomic Medicine, 4(1). https://doi.org/10.1038/s41525-019-0088-5

Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease

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Author: Keskitalo, Salla1; Haapaniemi, Emma M.2,3,4; Glumoff, Virpi5;
Organizations: 1Institute of Biotechnology, University of Helsinki, Helsinki, Finland
2Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway
3Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
4Biomedicum Stem Cell Center, University of Helsinki, Helsinki, Finland
5Research Unit of Biomedicine, Medical Microbiology and Immunology, University of Oulu, Oulu, Finland
6Päijät-Häme Central Hospital, Lahti, Finland
7Folkhälsan Institute of Genetics, Helsinki, Finland
8Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
9Research Programs Unit, Diabetes, and Obesity, University of Helsinki, Helsinki, Finland
10Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
11Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland
12Center for Hematology and Regenerative Medicine, Karolinska Institutet, Huddinge, Sweden
13Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
14Rare Disease Center, Hospital for Children and Adolescents and Adult Immunodeficiency Unit, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
15Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
16Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland
17School of Basic and Medical Biosciences, King’s College London, Guy’s Hospital, London, UK
18Hospital for Children and Adolescents, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.8 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019081524259
Language: English
Published: Springer Nature, 2019
Publish Date: 2019-08-15
Description:

Abstract

Mutations in several proteins functioning as endolysosomal components cause monogenic autoimmune diseases, of which pathogenesis is linked to increased endoplasmic reticulum stress, inefficient autophagy, and defective recycling of immune receptors. We report here a heterozygous TOM1 p.G307D missense mutation, detected by whole-exome sequencing, in two related patients presenting with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. The index patient suffered from recurrent respiratory tract infections and oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia, as well as an antibody deficiency. Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris. Consistent with previous knowledge on TOM1 protein function, we detected impaired autophagy and enhanced susceptibility to apoptosis in patient-derived cells. In addition, we noted diminished STAT and ERK1/2 signaling in patient fibroblasts, as well as poor IFN-γ and IL-17 secretion in T cells. The mutant TOM1 failed to interact with TOLLIP, a protein required for IL-1 recycling, PAMP signaling and autophagosome maturation, further strengthening the link between the candidate mutation and patient pathophysiology. In sum, we report here an identification of a novel gene, TOM1, associating with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. Other patient cases from unrelated families are needed to firmly establish a causal relationship between the genotype and the phenotype.

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Series: npj genomic medicine
ISSN: 2056-7944
ISSN-E: 2056-7944
ISSN-L: 2056-7944
Volume: 4
Article number: 14
DOI: 10.1038/s41525-019-0088-5
OADOI: https://oadoi.org/10.1038/s41525-019-0088-5
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: The Academy of Finland, Finnish Medical Foundation, Sigrid Juselius Foundation, Karolinska Institutet Research Foundation, Swedish Research Council, and Strategic Research Program in Diabetes supported this work.
Copyright information: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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