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Marfan syndrome: fibrillin expression and microfibrillar abnormalities in a family with predominant ocular defects
C M Kielty1, S J Davies, J E Phillips
1School of Biological Sciences, University of Manchester, UK.
Abstract:
We have found abnormal fibrillin microfibrils isolated from tissues and cell cultures from two cousins with Marfan syndrome whose major clinical abnormality is bilateral ectopia lentis, but who also have skeletal involvement but no cardiovascular defects. Ultrastructural analysis of ciliary zonules showed the presence of abundant loose microfibril bundles which in many places appeared disorganised. Microfibrils isolated from ciliary zonules and vitreous were highly fragmented when examined by rotary shadowing electron microscopy. Investigation of microfibrils elaborated by patient dermal fibroblasts showed remarkable variations in periodicity and packing. The synthesis and secretion of fibrillin by these cells was confirmed electrophoretically with the identification of metabolically labelled immunoprecipitated fibrillin (M(r) 300,000) in medium and cell layer compartments. These data show that fibrillin expression is normal but that assembled microfibrils are manifestly abnormal both morphologically and functionally. The occurrence of microfibrils with variable periodicities and susceptibility to fragmentation suggests that structural weakness is probably the primary cause of lens dislocation in these patients.
Insights
Marfan syndrome patients showed abnormal fibrillin microfibrils, impacting lens and skeletal structure. Despite normal fibrillin production, microfibril defects suggest a primary cause for lens dislocation in this genetic disorder.
Area of Science:
- Genetics and Molecular Biology
- Ophthalmology
- Rheumatology
Background:
- Marfan syndrome is a genetic connective tissue disorder.
- Clinical manifestations vary, including skeletal, ocular, and cardiovascular defects.
- Fibrillin microfibrils are crucial components of connective tissues.
Purpose of the Study:
- To investigate the structural and functional integrity of fibrillin microfibrils in Marfan syndrome patients.
- To determine if fibrillin synthesis or assembly is affected in patients with ectopia lentis and skeletal involvement.
- To elucidate the molecular basis of lens dislocation in Marfan syndrome.
Main Methods:
- Ultrastructural analysis of ciliary zonules and vitreous using electron microscopy.
- Isolation and characterization of microfibrils from patient tissues and cell cultures.
- Analysis of fibrillin synthesis and secretion by patient dermal fibroblasts using electrophoresis and metabolic labeling.
Main Results:
- Abnormal, disorganized, and fragmented fibrillin microfibrils were observed in patient tissues.
- Microfibrils elaborated by patient fibroblasts exhibited variable periodicity and packing.
- Fibrillin synthesis and secretion were confirmed to be normal, indicating an assembly defect.
Conclusions:
- Marfan syndrome in these patients is characterized by morphologically and functionally abnormal fibrillin microfibrils.
- The observed microfibril abnormalities, including fragmentation and variable periodicity, suggest structural weakness.
- This structural weakness of microfibrils is likely the primary cause of lens dislocation (ectopia lentis) in these individuals.