Journal
EMBO MOLECULAR MEDICINE
Volume 14, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202114904
Keywords
CAOP; electron transfer flavoprotein; MBTPS1; mitochondrial respiratory chain reaction
Categories
Funding
- National Nature Science Foundation of China [81874239, 81874252, 82073422, 81630083]
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In this study, we identified a new entity named cataract, alopecia, oral mucosal disorder, and psoriasis-like (CAOP) syndrome in two unrelated patients. Patient 1 showed no response to regular treatment. We discovered that CAOP syndrome was caused by a recessive defect in the MBTPS1 gene, which resulted in mitochondrial abnormalities. Furthermore, we found that riboflavin supplementation improved mitochondrial dysfunction and inflammatory lesions in patient 1.
In this report, we discovered a new entity named cataract, alopecia, oral mucosal disorder, and psoriasis-like (CAOP) syndrome in two unrelated and ethnically diverse patients. Furthermore, patient 1 failed to respond to regular treatment. We found that CAOP syndrome was caused by an autosomal recessive defect in the mitochondrial membrane-bound transcription factor peptidase/site-1 protease (MBTPS1, S1P). Mitochondrial abnormalities were observed in patient 1 with CAOP syndrome. Furthermore, we found that S1P is a novel mitochondrial protein that forms a trimeric complex with ETFA/ETFB. S1P enhances ETFA/ETFB flavination and maintains its stability. Patient S1P variants destabilize ETFA/ETFB, impair mitochondrial respiration, decrease fatty acid beta-oxidation activity, and shift mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis. Mitochondrial dysfunction and inflammatory lesions in patient 1 were significantly ameliorated by riboflavin supplementation, which restored the stability of ETFA/ETFB. Our study discovered that mutations in MBTPS1 resulted in a new entity of CAOP syndrome and elucidated the mechanism of the mutations in the new disease.
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