ANR POIKTMP-DP - Sandra Mercier (2025-2029)
Sandra Mercier is the scientific leader of an ANR-PRC project : POIKTMP-Deciphering Project: translational investigation of POIKTMP molecular pathogenesis caused by dominant FAM111B variants
Summary
Poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a rare and severe multisystem disorder caused by dominant variants in FAM111B, first described by the coordinating team in 2013. Disease mechanisms remain poorly understood due to limited knowledge of FAM111B function and the absence of relevant animal orthologs. Our preliminary studies showed that expression of human mutant FAM111B in zebrafish and mouse models recapitulates key muscle features observed in patients, supporting conserved FAM111B functions across species. We further demonstrated a dominant-negative effect of pathogenic variants and identified altered ubiquitin-proteasome system (UPS) regulation and impaired FAM111B interactions within a high-molecular-weight protein complex, suggesting a critical role of FAM111B in protein homeostasis. The POIKTMP-DP project combines expertise from four complementary teams in basic research, therapeutic innovation, and clinical care to develop a translational strategy for POIKTMP. Three objectives will be pursued: (1) deciphering FAM111B molecular functions through interactome mapping, proteomics, ChIP-seq, and transcriptomic analyses; (2) establishing innovative preclinical models, including patient-derived iPSC muscle organoids and an in vivo rAAV-FAM111B mouse model, to investigate disease mechanisms and therapeutic responses; and (3) developing targeted therapies based on the dominant-negative mechanism, including allele-specific antisense oligonucleotides and pre-mRNA trans-splicing approaches. POIKTMP-DP represents a pioneering effort to address a currently untreatable disorder. By integrating mechanistic studies, advanced disease models, and precision medicine approaches, this project aims to establish the foundations for targeted therapies for POIKTMP patients. More broadly, it may provide a transferable framework for other monogenic diseases caused by dominant-negative variants.
Summary
Poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a rare and severe multisystem disorder caused by dominant variants in FAM111B, first described by the coordinating team in 2013. Disease mechanisms remain poorly understood due to limited knowledge of FAM111B function and the absence of relevant animal orthologs. Our preliminary studies showed that expression of human mutant FAM111B in zebrafish and mouse models recapitulates key muscle features observed in patients, supporting conserved FAM111B functions across species. We further demonstrated a dominant-negative effect of pathogenic variants and identified altered ubiquitin-proteasome system (UPS) regulation and impaired FAM111B interactions within a high-molecular-weight protein complex, suggesting a critical role of FAM111B in protein homeostasis. The POIKTMP-DP project combines expertise from four complementary teams in basic research, therapeutic innovation, and clinical care to develop a translational strategy for POIKTMP. Three objectives will be pursued: (1) deciphering FAM111B molecular functions through interactome mapping, proteomics, ChIP-seq, and transcriptomic analyses; (2) establishing innovative preclinical models, including patient-derived iPSC muscle organoids and an in vivo rAAV-FAM111B mouse model, to investigate disease mechanisms and therapeutic responses; and (3) developing targeted therapies based on the dominant-negative mechanism, including allele-specific antisense oligonucleotides and pre-mRNA trans-splicing approaches. POIKTMP-DP represents a pioneering effort to address a currently untreatable disorder. By integrating mechanistic studies, advanced disease models, and precision medicine approaches, this project aims to establish the foundations for targeted therapies for POIKTMP patients. More broadly, it may provide a transferable framework for other monogenic diseases caused by dominant-negative variants.
Updated on 21 July 2026.