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Cosegregation of elastin-associated microfibrillar abnormalities with the Marfan phenotype in families
M Godfrey1, V Menashe, R G Weleber
1Portland Unit, Shriners Hospitals for Crippled Children, Portland.
Abstract:
The Marfan syndrome is a serious heritable connective-tissue disorder characterized primarily by ocular, cardiovascular, and musculoskeletal abnormalities but also involving multiple other tissues and organs of the body. Inherited as an autosomal dominant disorder, the etiology and pathogenesis of the Marfan syndrome are presently unknown. We have documented consistent apparent deficient content of elastin-associated microfibrillar fibers by indirect immunofluorescent (IF) studies of Marfan skin, as well as deficient accumulation of related fibrous materials in cultures of Marfan fibroblasts as compared with normal controls and patients with other heritable disorders of connective tissue. These data have suggested that abnormalities in the microfibrillar component of elastic-fiber systems may have a role in the etiology and pathogenesis of the Marfan syndrome. In the present study, we have analyzed the IF staining patterns of skin and fibroblast cultures from Marfan syndrome patients and normal first-degree relatives in nine Marfan kindreds. Three of these families had at least one affected individual in each of 2 generations, permitting intergenerational comparison of IF patterns. Six kindreds had one or more affected individuals in a single generation, making comparisons between siblings and/or parent-child possible. In all cases, IF abnormalities cosegregated with the Marfan phenotype and all nonaffected family members were normal. Within family groups containing more than one affected individual, the IF staining patterns were similar between affected patients. These data provide further confirmation of consistent and relatively specific deficiency of microfibrillar fibers in Marfan syndrome.
Insights
Marfan syndrome involves connective tissue abnormalities. Studies show a deficiency in microfibrillar fibers, suggesting their role in the disorder's cause and development.
Area of Science:
- Genetics
- Cell Biology
- Biochemistry
Background:
- Marfan syndrome is a heritable connective tissue disorder with diverse clinical manifestations.
- Its exact cause and development (etiology and pathogenesis) remain largely unknown.
- Previous studies suggested a potential role for microfibrillar components of elastic fibers.
Purpose of the Study:
- To investigate the microfibrillar component of elastic fibers in Marfan syndrome.
- To analyze immunofluorescent staining patterns in Marfan patients and their relatives.
- To confirm the association between microfibrillar deficiency and Marfan syndrome.
Main Methods:
- Indirect immunofluorescence (IF) studies on skin and fibroblast cultures.
- Analysis of nine Marfan kindreds with intergenerational comparisons.
- Comparison of staining patterns between affected individuals, unaffected relatives, and controls.
Main Results:
- Consistent deficiency in elastin-associated microfibrillar fibers was observed in Marfan syndrome.
- Abnormal IF staining patterns segregated with the Marfan phenotype across generations.
- Unaffected family members exhibited normal IF staining patterns.
Conclusions:
- Abnormalities in microfibrillar fibers are consistently found in Marfan syndrome.
- These findings support a role for microfibrillar deficiency in the etiology and pathogenesis of Marfan syndrome.
- The observed deficiency is relatively specific to Marfan syndrome.