Ubiquitin-proteasome system dysregulation in FAM111B-related poikiloderma and phenotypic spectrum expansion: new case reports and long-term follow-up.

Abstract

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. 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. 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. These findings highlight a dysfunctional UPS as a potential central driver of POIKTMP's molecular pathogenesis, presenting promising therapeutic avenues. 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.