S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis‐like syndrome

EMBO Molecular Medicine

Yiran Guo¹  Zhen Wang²  Chaolan Pan³  Jianying Liang³  Cheng Ni³  Xiaoxiao Wang³  Jia Zhang³  Ming Li³  Zhirong Yao³  Fuying Chen³  Ruhong Cheng³  Yumeng Wang³  Alejandra G de Alba Campomanes⁴  Yi Zhou⁵  Erin F Mathes⁶  Stephanie Htun⁷  Anne M Slavotinek⁷  Y Eugene Chin⁸  Si Zhang⁹  She Chen⁹  Jinke Cheng^1,10 

[1] Center for Data Driven Discovery in Biomedicine Children’s Hospital of Philadelphia PA USA;Department of Dermatology Children's Hospital of Shanghai Jiaotong University Shanghai China;Department of Dermatology Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China;Department of Ophthalmology University of California San Francisco CA USA;Department of gastroenterology Zhongshan Hospital Fudan University Shanghai China;Departments of Dermatology and Pediatrics University California San Francisco CA USA;Division of Genetics Department of Pediatrics University of California San Francisco San Francisco CA USA;Instituteof Health Sciences, Chinese Academy of Sciences Shanghai Jiaotong University School of Medicine Shanghai China;NHC Key Laboratory of Glycoconjugate Research Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Fudan University Shanghai China;Shanghai Key Laboratory for Tumor Microenvironment and Inflammation Department of Biochemistry and Molecular Cell Biology Shanghai Jiao Tong University School of Medicine Shanghai China;

关键词: CAOP;    electron transfer flavoprotein;    MBTPS1;    mitochondrial respiratory chain reaction;   

DOI  :  10.15252/emmm.202114904

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown