Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome

Daniel P. Judge, Nancy J. Biery, Douglas R. Keene, Jessica Geubtner, Loretha Myers, David L. Huso, Lynn Sakai, Harry C. Dietz

Research output: Contribution to journalArticle

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Abstract

Marfan syndrome is a connective tissue disorder caused by mutations in the gene encoding fibrillin-1 (FBN1). A dominant-negative mechanism has been inferred based upon dominant inheritance, mulitimerization of monomers to form microfibrils, and the dramatic paucity of matrix-incorporated fibrillin-1 seen in heterozygous patient samples. Yeast artificial chromosome-based transgenesis was used to overexpress a disease-associated mutant form of human fibrillin-1 (C1663R) on a normal mouse background. Remarkably, these mice failed to show any abnormalities of cellular or clinical phenotype despite regulated overexpression of mutant protein in relevant tissues and developmental stages and direct evidence that mouse and human fibrillin-1 interact with high efficiency. Immunostaining with a human-specific mAb provides what we believe to be the first demonstration that mutant fibrillin-1 can participate in productive microfibrillar assembly. Informatively, use of homologous recombination to generate mice heterozygous for a comparable missense mutation (C1039G) revealed impaired microfibrillar deposition, skeletal deformity, and progressive deterioration of aortic wall architecture, comparable to characteristics of the human condition. These data are consistent with a model that invokes haploinsufficiency for WT fibrillin-1, rather than production of mutant protein, as the primary determinant of failed microfibrillar assembly. In keeping with this model, introduction of a WT FBN1 transgene on a heterozygous C1039G background rescues aortic phenotype.

Original languageEnglish (US)
Pages (from-to)172-181
Number of pages10
JournalJournal of Clinical Investigation
Volume114
Issue number2
DOIs
StatePublished - Jul 1 2004

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Haploinsufficiency
Marfan Syndrome
Mutant Proteins
Yeast Artificial Chromosomes
Microfibrils
Phenotype
Gene Transfer Techniques
Homologous Recombination
Missense Mutation
Fibrillin-1
Transgenes
Connective Tissue
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Judge, D. P., Biery, N. J., Keene, D. R., Geubtner, J., Myers, L., Huso, D. L., ... Dietz, H. C. (2004). Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. Journal of Clinical Investigation, 114(2), 172-181. https://doi.org/10.1172/JCI200420641

Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. / Judge, Daniel P.; Biery, Nancy J.; Keene, Douglas R.; Geubtner, Jessica; Myers, Loretha; Huso, David L.; Sakai, Lynn; Dietz, Harry C.

In: Journal of Clinical Investigation, Vol. 114, No. 2, 01.07.2004, p. 172-181.

Research output: Contribution to journalArticle

Judge, Daniel P. ; Biery, Nancy J. ; Keene, Douglas R. ; Geubtner, Jessica ; Myers, Loretha ; Huso, David L. ; Sakai, Lynn ; Dietz, Harry C. / Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. In: Journal of Clinical Investigation. 2004 ; Vol. 114, No. 2. pp. 172-181.
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