Background and Aims

We evaluated two Finnish patients, a mother and her son, presenting with early-onset autoimmunity and combined immunodeficiency. The mother suffered from recurrent respiratory tract infections, atopic eczema, and oligoarthritis since childhood and later developed chronic diarrhea and persistent EBV-viremia. Her son had growth retardation, autoimmune enteropathy, eczema, and interstitial lung disease. Both patients displayed hypogammaglobulinemia and impaired regulatory T cell function. The son died at the age of 10 due to pulmonary complications following allogeneic hematopoietic stem cell transplantation. 

Whole-exome sequencing of these patients revealed a heterozygous variant (p.G307D) in the target of myb1 membrane trafficking protein (TOM1) -gene. TOM1 is known to be involved in autophagy, endosomal trafficking, and receptor recycling, all of which have been implicated in monogenic autoimmune diseases. 

Our objective was to elucidate the mechanisms by which this mutation causes the phenotype seen in these patients.

Methods

Fluorescence microscopy and western blotting were utilized to study autophagy and innate immune signaling in primary skin fibroblasts and lymphoblasts from the patients carrying TOM1 mutation.

Results

TOM1 mutant cells displayed a higher level of autophagy compared to wild-type cells. Amino acid starvation led to a significantly higher amount of autophagosomes compared to healthy control cells. When returned in complete culture media, patient cells showed slower autophagosome clearance, suggesting delayed degradation rather than enhanced autophagosome formation.

Conclusions

TOM1 mutation carried by the patients causes defective autophagosome clearance and is likely to contribute to the clinical phenotype of these patients.