%0 Case Reports
%T S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome.
%A Chen F
%A Ni C
%A Wang X
%A Cheng R
%A Pan C
%A Wang Y
%A Liang J
%A Zhang J
%A Cheng J
%A Chin YE
%A Zhou Y
%A Wang Z
%A Guo Y
%A Chen S
%A Htun S
%A Mathes EF
%A de Alba Campomanes AG
%A Slavotinek AM
%A Zhang S
%A Li M
%A Yao Z
%J EMBO Mol Med
%V 14
%N 5
%D 05 2022 9
%M 35362222
%F 14.26
%R 10.15252/emmm.202114904
%X 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 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.