Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease

Salla Keskitalo, Emma M. Haapaniemi, Virpi Glumoff, Xiaonan Liu, Ville Lehtinen, Christopher Fogarty, Hanna Rajala, Samuel C. Chiang, Satu Mustjoki, Panu Kovanen, Jouko Lohi, Yenan T. Bryceson, Mikko Seppänen, Juha Kere, Kaarina Heiskanen, Markku Varjosalo

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

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.
Alkuperäiskielienglanti
LehtiNpj genomic medicine
Vuosikerta4
Numero1
ISSN2056-7944
DOI - pysyväislinkit
TilaJulkaistu - 27 heinäkuuta 2019
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 1184 Genetiikka, kehitysbiologia, fysiologia

Lainaa tätä

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. / Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease. Julkaisussa: Npj genomic medicine. 2019 ; Vuosikerta 4, Nro 1.
@article{75e3a05f251c41518fa678bbb7c31cb7,
title = "Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease",
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 = "1184 Genetics, developmental biology, physiology",
author = "Salla Keskitalo and Haapaniemi, {Emma M.} and Virpi Glumoff and Xiaonan Liu and Ville Lehtinen and Christopher Fogarty and Hanna Rajala and Chiang, {Samuel C.} and Satu Mustjoki and Panu Kovanen and Jouko Lohi and Bryceson, {Yenan T.} and Mikko Sepp{\"a}nen and Juha Kere and Kaarina Heiskanen and Markku Varjosalo",
year = "2019",
month = "7",
day = "27",
doi = "10.1038/s41525-019-0088-5",
language = "English",
volume = "4",
journal = "Npj genomic medicine",
issn = "2056-7944",
publisher = "Springer Nature in partnership with the Center of Excellence in Genomic Medicine Research",
number = "1",

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Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease. / 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.

julkaisussa: Npj genomic medicine, Vuosikerta 4, Nro 1, 27.07.2019.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

TY - JOUR

T1 - Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease

AU - Keskitalo, Salla

AU - Haapaniemi, Emma M.

AU - Glumoff, Virpi

AU - Liu, Xiaonan

AU - Lehtinen, Ville

AU - Fogarty, Christopher

AU - Rajala, Hanna

AU - Chiang, Samuel C.

AU - Mustjoki, Satu

AU - Kovanen, Panu

AU - Lohi, Jouko

AU - Bryceson, Yenan T.

AU - Seppänen, Mikko

AU - Kere, Juha

AU - Heiskanen, Kaarina

AU - Varjosalo, Markku

PY - 2019/7/27

Y1 - 2019/7/27

N2 - 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.

AB - 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.

KW - 1184 Genetics, developmental biology, physiology

U2 - 10.1038/s41525-019-0088-5

DO - 10.1038/s41525-019-0088-5

M3 - Article

VL - 4

JO - Npj genomic medicine

JF - Npj genomic medicine

SN - 2056-7944

IS - 1

ER -