Yao Zhirong/Li Ming/Zhang Si team discovered a new disease-CAOP syndrome causative gene MBTPS1 and its pathogenic mechanism

Cataract-alopecia-oral mucosal disease-psoriasis-like syndrome (CAOP syndrome) is an extremely rare disorder characterized by premature bilateral cataracts, generalized non-scarring alopecia, oral mucosal disease, and Severe psoriasis-like skin lesio.

After more than ten years of research, the team of Yao Zhirong/Li Ming/Zhang Si from Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine reported for the first time that membrane-bound transcription factor peptidase/site 1 protease (MBTPS1/S1P) is the causative gene of CAOP syndro.

The research results were recently published in the journal EMBO Molecular Medici.

research material

In this study, the researchers constructed a skin-specific Mbtps1 conditional knockout mouse model and a Mbtps1 knockdown mbtps1-MO ​​zebrafish model (the Mptps1 conditional knockout mouse model was provided by Saiye Biotec.

Technical method

They employed a number of techniques in their research, including whole-exome sequencing analysis, western blotting, and protein stability analys.

Technical route

Research result

Sequencing identifies pathogenic variants in CAOP syndrome

We identified two sporadic cases of CAOP syndrome, a 14-year-old Chinese boy (patient 1) and a 5-year-old Spanish girl (patient

Given the significantly increased mitochondrial numbers and symptoms of abnormal mitochondrial morphology in Patient 1, the researchers wanted to understand whether this was caused by S1P deficien.

S1P interacts with ETFA and ETFB

Through a series of analyses, the researchers showed that S1P is a novel mitochondrial protein that exists within the mitochondrial matrix spa.

After screening for interacting proteins of S1P, the researchers performed bioinformatics analysis of potential binding protei.

FigureS1P forms a trimeric complex with ETFA and ETFB proteins

Abnormal S1P impairs mitochondrial respiration

The researchers found that ETFA and ETFB protein levels decreased in the skin biopsy of Patient 1, but mRNA expression did not change significant.

Compared with wild-type S1P, the binding of mutant S1P to ETFA and ETFB was reduced, suggesting that the MBTPS1 variant lost the ability to form a trimeric complex with E.

Measurement of oxygen consumption rate (OCR) showed that mitochondrial respiration was reduced in MBTPS1-KO HaCaT cells compared with control cel.

FigureS1P dysfunction disrupts ETF luteinization and stability

Riboflavin therapy reduces inflammatory lesions in patients

Given that MBTPS1 mutations destabilize ETFs, the researchers propose the use of riboflavin to reverse mitochondrial abnormalities and treat CAOP syndro.

Patient 1 did not respond to various treatment regimens prior to oral riboflav.

Analysis conclusion

FigureThe putative mechanism of S1P regulation of cellular respiration

Overall, this study shows that MBTPS1 variants cause CAOP syndro.

Original text retrieval

Chen F, Ni C, Wang X, et .