Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease

NPJ Genom Med. 2019 Jun 27;4:14. doi: 10.1038/s41525-019-0088-5.

Salla Keskitalo ^# ¹, Emma M Haapaniemi ^# ² ³ ⁴, Virpi Glumoff ⁵, Xiaonan Liu ¹, Ville Lehtinen ⁶, Christopher Fogarty ⁷ ⁸ ⁹, Hanna Rajala ¹⁰ ¹¹, Samuel C Chiang ¹², Satu Mustjoki ¹⁰ ¹¹, Panu Kovanen ¹³, Jouko Lohi ¹³, Yenan T Bryceson ³, Mikko Seppänen ¹⁴, Juha Kere ⁷ ¹⁵ ¹⁶ ¹⁷, Kaarina Heiskanen ¹⁸, Markku Varjosalo ¹

Affiliations

1 1Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
2 2Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway.
3 3Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
4 4Biomedicum Stem Cell Center, University of Helsinki, Helsinki, Finland.
5 5Research Unit of Biomedicine, Medical Microbiology and Immunology, University of Oulu, Oulu, Finland.
6 6Päijät-Häme Central Hospital, Lahti, Finland.
7 7Folkhälsan Institute of Genetics, Helsinki, Finland.
8 8Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
9 9Research Programs Unit, Diabetes, and Obesity, University of Helsinki, Helsinki, Finland.
10 10Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
11 11Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
12 12Center for Hematology and Regenerative Medicine, Karolinska Institutet, Huddinge, Sweden.
13 13Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
14 14Rare Disease Center, Hospital for Children and Adolescents and Adult Immunodeficiency Unit, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
15 15Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
16 16Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
17 17School of Basic and Medical Biosciences, King's College London, Guy's Hospital, London, UK.
18 18Hospital for Children and Adolescents, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
# Contributed equally.

PMID: 31263572 DOI: 10.1038/s41525-019-0088-5

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.

Keywords

Diseases; Immunological disorders.

Name
Email *

	Sorry, but the email address you supplied was invalid.