Ubiquitin-proteasome system dysregulation in FAM111B-related poikiloderma and phenotypic spectrum expansion: new case
Virginie Vignard1, Mike Maillasson2, Anne Bigot3
1Nantes Université, CNRS, INSERM, l'institut du Thorax, Nantes 44000, France.
Insights
Hereditary fibrosing disorder POIKTMP, caused by FAM111B mutations, involves a dysfunctional ubiquitin-proteasome system (UPS). This discovery offers new therapeutic targets for POIKTMP patients.
Area of Science:
- Genetics and Molecular Biology
- Rare Diseases
- Cellular Biology
Background:
- Poikiloderma, hereditary fibrosing, with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is a rare genetic disorder linked to FAM111B gene mutations.
- The molecular mechanisms underlying POIKTMP are not well understood.
- FAM111B, a serine protease, has roles beyond cancer, as indicated by germline variants not consistently associated with tumors.
Purpose of the Study:
- To elucidate the molecular pathogenesis of POIKTMP.
- To expand the understanding of the clinical spectrum and genetic basis of POIKTMP.
Main Methods:
- Clinical data from 41 POIKTMP patients, including 4 new cases, were compiled and compared.
- Functional studies utilized omics technologies on patient-derived cells with FAM111B missense variants.
Main Results:
- The POIKTMP phenotype includes renal failure, dental anomalies, hypoparathyroidism, and neuropathy.
- FAM111B variants in the D-box domain correlate with a more severe clinical presentation.
- Loss of FAM111B expression disrupts the ubiquitin-proteasome system (UPS), increasing ubiquitin-protein conjugates and inducing a type I interferon signature.
Conclusions:
- A dysfunctional UPS is implicated as a key driver in POIKTMP molecular pathogenesis.
- These findings suggest potential therapeutic strategies targeting UPS dysfunction for POIKTMP.
Background:
Poikiloderma, hereditary fibrosing, with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is a rare genetic multisystemic fibrosing disorder caused by FAM111B gene mutations. Given its rarity, the molecular underpinnings of POIKTMP remain elusive. FAM111B, a trypsin-like serine protease, initially studied in cancer, exhibits germline variants not consistently linked to tumours, suggesting broader functions beyond cell proliferation.
Methods:
In this study, we compiled and compared the clinical features of 41 POIKTMP patients, which included the description of 4 newly identified cases. Functional studies involved the exploration of patient-derived cells carrying FAM111B missense variants using omics technologies.
Findings:
Our results show that the phenotypic spectrum of POIKTMP encompassed renal failure, dental anomalies, hypoparathyroidism, and potentially neuropathy. Notably, variants clustering within the D-box domain of FAM111B protein tend to present a more severe phenotype. Most importantly, loss of FAM111B expression perturbed ubiquitin-proteasome system (UPS) function, leading to increased content of ubiquitin-protein conjugates and a sterile type I interferon signature.
Interpretation:
These findings highlight a dysfunctional UPS as a potential central driver of POIKTMP's molecular pathogenesis, presenting promising therapeutic avenues.
Funding:
Association Française contre les Myopathies (AFM - 20760), Fondation Génavie (657298), Fondation Thellie, I-SITE NExT Junior Talent, Biogenouest, Infrastructures en Biologie Santé et Agronomie (IBiSA) and Conseil Régional de Bretagne.
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