MBTPS1 Defects Cause a New Entity of Cataract, Alopecia, Oral Mucosal Disorder, Psoriasis-like Syndrome. MBTPS1 variant

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, the 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 the patient 1 with CAOP syndrome. Furthermore, we found that S1P is a novel mitochondrial protein that forms a trimetric complex with ETFA/ETFB. S1P enhances ETFA/ETFB flavination and maintains their stability. Patient S1P variants destabilize ETFA/ETFB, impair mitochondrial respiration, decrease fatty acid β-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.