| Molecular level | Specific mechanism/pathway | Biological process affected | Molecular consequences in MFLS | Suggested GO terms | Key evidence |
|---|---|---|---|---|---|
| Protein | C-terminal **FBN1** truncation due to variants near exons/intron 65 that escape nonsense-mediated decay | Extracellular matrix structural organization; profibrillin processing | Production of truncated fibrillin-1 rather than simple haploinsufficiency; altered extreme C-terminal domain and loss/disruption of asprosin-generating region | GO:0030198 extracellular matrix organization; GO:0006508 proteolysis; GO:0005634? not applicable | Variants near the 3' terminus generate premature stop codons that escape NMD and yield truncated fibrillin-1; exon 65 skipping was experimentally confirmed for c.8226+5G>A (pqac-00000003, pqac-00000007, pqac-00000018, pqac-00000019, pqac-00000026) |
| Protein | Loss of normal fibrillin-1 microfibril function | Microfibril assembly; elastic fiber formation | Reduced functional microfibrils and compromised extracellular scaffold properties | GO:0001525 angiogenesis; GO:0030199 collagen fibril organization; GO:0072358 cardiovascular system development | Defective fibrillin-1 reduces fully functional microfibrils and disrupts connective-tissue support, contributing to marfanoid manifestations and adipose tissue abnormalities (pqac-00000006, pqac-00000009, pqac-00000011, pqac-00000012) |
| Protein/endocrine | **Asprosin deficiency** from disruption of the C-terminal profibrillin cleavage product | Hormone secretion; glucose homeostasis; appetite regulation | Reduced asprosin is inferred to contribute to poor appetite, low glucose/insulin tone, leanness, and lipodystrophic metabolic state | GO:0042593 glucose homeostasis; GO:2000253 positive regulation of feeding behavior; GO:1904179 positive regulation of gluconeogenesis | Asprosin is a C-terminal fibrillin-1-derived hormone; in MFLS/NPS-like states, loss of this region is linked to hypophagia and extreme leanness, and the 2023 case reported poor appetite (pqac-00000006, pqac-00000008, pqac-00000012, pqac-00000018) |
| Cellular | Dysregulated **TGF-β** bioavailability/signaling secondary to defective fibrillin-1/LTBP interactions | Regulation of TGF-β signaling; osteoblast maturation; adipose development | Increased active TGF-β signaling, with downstream effects on adipogenesis, connective tissue biology, and skeletal development | GO:0007179 transforming growth factor beta receptor signaling pathway; GO:0001649 osteoblast differentiation; GO:0045599 negative regulation of fat cell differentiation | Fibrillin-1 normally regulates TGF-β bioavailability; defective fibrillin-1 increases active TGF-β. Reviews note this likely contributes to bone and fat phenotypes in MFLS (pqac-00000009, pqac-00000030, pqac-00000031, pqac-00000032) |
| Cellular | Impaired adipogenesis in white adipose tissue | Adipocyte differentiation; lipid storage cell development | Reduced subcutaneous adipose tissue and severe partial/generalized lipodystrophy | GO:0045444 fat cell differentiation; GO:0050872 white fat cell differentiation; GO:1903444 regulation of adipose tissue development | MFLS is consistently associated with generalized/subcutaneous fat loss; mechanistic reviews link fibrillin-1 defects, altered TGF-β signaling, and asprosin disruption to impaired adipogenesis (pqac-00000006, pqac-00000007, pqac-00000011, pqac-00000020) |
| Tissue | Altered extracellular matrix mechanical properties in adipose tissue | Cell-matrix interaction; tissue morphogenesis | Fibrotic/rigid ECM environment around adipocytes that may impede normal adipose expansion and signaling | GO:0031012 extracellular matrix; GO:0009653 anatomical structure morphogenesis; GO:0009611 response to wounding | Reviews suggest altered mechanical properties of fibrillin-deficient ECM may be a major driver of adipose dysfunction, possibly more important than TGF-β alone in explaining reduced body fat (pqac-00000011, pqac-00000029) |
| Tissue | Impaired transport/signaling milieu in adipose tissue | Insulin receptor signaling; nutrient/hormone responsiveness | Mechanical barrier and ECM remodeling may impair glucose/insulin access and downstream signaling, predisposing to insulin signaling defects | GO:0046627 negative regulation of insulin receptor signaling pathway; GO:0006006 glucose metabolic process | Fibrillin-1-related adipose ECM abnormalities are proposed to impair insulin signaling and contribute to metabolic dysfunction in lipodystrophy syndromes (pqac-00000008, pqac-00000011) |
| Systemic | Combined connective tissue and adipose endocrine disorder | Growth, musculoskeletal development, ocular/cardiovascular homeostasis, energy balance | Explains the syndromic triad of marfanoid habitus, progeroid appearance from fat loss, and lipodystrophy with variable Marfan-like ocular/cardiovascular features | GO:0048731 system development; GO:0003013 circulatory system process; GO:0001654 eye development | Clinical phenotype includes fetal growth retardation/prematurity, lack of subcutaneous fat, long fingers, myopia, and variable aortic/mitral findings, consistent with a multisystem fibrillinopathy plus endocrine-metabolic disturbance (pqac-00000005, pqac-00000018, pqac-00000019, pqac-00000028) |
| Systemic/model-supported | Asprosin-related energy balance defect demonstrated in animal models of Fbn1 exon 65 junction disruption | Feeding behavior; body weight regulation; diabetes susceptibility | Heterozygous mice show hypophagia, reduced adiposity, and resistance to diet-induced obesity/diabetes; recombinant asprosin rescues hypophagia | GO:2000253 positive regulation of feeding behavior; GO:0042593 glucose homeostasis; GO:0040018 positive regulation of multicellular organism growth | Recent model data support a causal contribution of asprosin deficiency to appetite and adiposity phenotypes relevant to MFLS (pqac-00000015) |


*Table: This table summarizes the main molecular, cellular, tissue, and systemic mechanisms currently implicated in Marfanoid-Progeroid-Lipodystrophy Syndrome. It is useful for linking FBN1 C-terminal variants to extracellular matrix dysfunction, altered TGF-beta signaling, asprosin deficiency, impaired adipogenesis, and the resulting multisystem phenotype.*