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

Fuying Chen; Cheng Ni; Xiaoxiao Wang; Ruhong Cheng; Chaolan Pan; Yumeng Wang; Jianying Liang; Jia Zhang; Jinke Cheng; Y Eugene Chin; Yi Zhou; Zhen Wang; Yiran Guo; She Chen; Stephanie Htun; Erin F Mathes; Alejandra G de Alba Campomanes; Anne M Slavotinek; Si Zhang; Ming Li; Zhirong Yao

doi:10.15252/emmm.202114904

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

EMBO Mol Med. 2022 May 9;14(5):e14904. doi: 10.15252/emmm.202114904. Epub 2022 Apr 1.

Authors

Fuying Chen^#^{1

2}, Cheng Ni^#^{1

2}, Xiaoxiao Wang^#^{1

2}, Ruhong Cheng^#^{1

2}, Chaolan Pan^#^{1

2}, Yumeng Wang^{1

2}, Jianying Liang¹, Jia Zhang¹, Jinke Cheng³, Y Eugene Chin⁴, Yi Zhou⁵, Zhen Wang⁶, Yiran Guo⁷, She Chen⁸, Stephanie Htun⁹, Erin F Mathes¹⁰, Alejandra G de Alba Campomanes¹¹, Anne M Slavotinek⁹, Si Zhang⁸, Ming Li^{1

2}, Zhirong Yao^{1

2}

Affiliations

¹ Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
² Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
³ Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Instituteof Health Sciences, Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁵ Department of gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Department of Dermatology, Children's Hospital of Shanghai Jiaotong University, Shanghai, China.
⁷ Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, PA, USA.
⁸ NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁹ Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Departments of Dermatology and Pediatrics, University California, San Francisco, CA, USA.
¹¹ Department of Ophthalmology, University of California, San Francisco, CA, USA.

^# Contributed equally.

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.

Keywords: CAOP; MBTPS1; electron transfer flavoprotein; mitochondrial respiratory chain reaction.

Publication types

Case Reports

MeSH terms

Alopecia / genetics
Cataract* / genetics
Electron-Transferring Flavoproteins / genetics
Electron-Transferring Flavoproteins / metabolism
Humans
Psoriasis*
Riboflavin / metabolism

Substances

Electron-Transferring Flavoproteins
Riboflavin