Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease

• Published in: Npj genomic medicine 2019-06, Vol.4 (1), p.14-7, Article 14
• Main Authors: Keskitalo, Salla, Haapaniemi, Emma M., Glumoff, Virpi, Liu, Xiaonan, Lehtinen, Ville, Fogarty, Christopher, Rajala, Hanna, Chiang, Samuel C., Mustjoki, Satu, Kovanen, Panu, Lohi, Jouko, Bryceson, Yenan T., Seppänen, Mikko, Kere, Juha, Heiskanen, Kaarina, Varjosalo, Markku
• Format: Article
• Language: English
• Subjects: 692/699; 692/699/249; Autophagy; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Case Report; Gene Function; Gene Therapy; Human Genetics; Internal Medicine; Mutation
• ISSN: 2056-7944; 2056-7944
• DOI: 10.1038/s41525-019-0088-5

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.