An Integrative Genotyping and Gene Expression Profiling of the Mutated Human FAM111B Gene and Fibrosis-Associated Pathway in the POIKTMP Syndrome.

Abstract

Poikiloderma with tendon contracture, myopathy and pulmonary fibrosis (POIKTMP) is a rare hereditary disorder caused by mutations in the FAM111B gene, characterised by multi-organ fibrosis, particularly affecting the lungs. This study investigates the molecular mechanisms of fibrosis in POIKTMP through genotyping and gene expression profiling of FAM111B and associated fibrotic pathways. Post-mortem formalin-fixed paraffin-embedded (FFPE) tissues from a POIKTMP patient and healthy controls were analysed. Genomic DNA was extracted, confirming the FAM111B Y621D mutation via Sanger sequencing. RT-qPCR and the RT² Profiler PCR Array were used to evaluate fibrosis-related gene expression in lung and skin tissues. Disease and pathway enrichment analyses were conducted using Metascape, GeneMANIA and Enrichr tools. The FAM111B Y621D mutation was validated, and gene expression profiling revealed significant upregulation of fibrotic markers, such as TGFβ-3, PDGFA, ITGB1, MMP3, MMP13 and CCN2 in the lungs, and COL3A1 and THBS2 in the skin. Pathway enrichment analysis linked FAM111B to extracellular matrix remodelling, cell adhesion, and cancer. These findings suggest that FAM111B mutations drive fibrosis through dysregulated gene networks, highlighting potential therapeutic targets for POIKTMP and related fibrotic diseases. Further research is required to understand FAM111B's role in fibrosis fully.