The molecular genetics of Marfan syndrome and related microfibrillopathies

Peter N. Robinson, Maurice Godfrey

Research output: Contribution to journalReview article

218 Citations (Scopus)

Abstract

Mutations in the gene for fibrillin-1 (FBN1) have been shown to cause Marfan syndrome, an autosomal dominant disorder of connective tissue characterised by pleiotropic manifestations involving primarily the ocular, skeletal, and cardiovascular systems. Fibrillin-1 is a major component of the 10-12 nm microfibrils, which are thought to play a role in tropoelastin deposition and elastic fibre formation in addition to possessing an anchoring function in some tissues. Fibrillin-1 mutations have also been found in patients who do not fulfil clinical criteria for the diagnosis of Marfan syndrome, but have related disorders of connective tissue, such as isolated ectopia lentis, familial aortic aneurysm, and Marfan-like skeletal abnormalities, so that Marfan syndrome may be regarded as one of a range of type 1 fibrillinopathies. There appear to be no particular hot spots since mutations are found throughout the entire fibrillin-1 gene. However, a clustering of mutations associated with the most severe form of Marfan syndrome, neonatal Marfan syndrome, has been noted in a region encompassing exons 24 to 32. The gene for fibrillin-2 (FBN2) is highly homologous to FBN1, and mutations in FBN2 have been shown to cause a phenotypically related disorder termed congenital contractural arachnodactyly. Since mutations in the fibrillin genes are likely to affect the global function of the microfibrils, the term microfibrillopathy may be the most appropriate to designate the spectrum of disease associated with dysfunction of these molecules. The understanding of the global and the molecular functions of the fibrillin containing microfibrils is still incomplete and, correspondingly, no comprehensive theory of the pathogenesis of Marfan syndrome has emerged to date. Many, but not all, fibrillin-1 gene mutations are expected to exert a dominant negative effect, whereby mutant fibrillin monomers impair the global function of the microfibrils. In this paper we review the molecular physiology and pathophysiology of Marfan syndrome and related microfibrillopathies.

Original languageEnglish (US)
Pages (from-to)9-25
Number of pages17
JournalJournal of medical genetics
Volume37
Issue number1
StatePublished - May 18 2000

Fingerprint

Marfan Syndrome
Molecular Biology
Microfibrils
Mutation
Genes
Connective Tissue
Tropoelastin
Elastic Tissue
Cardiovascular System
Cluster Analysis
Fibrillin-1
Exons
Fibrillins

Keywords

  • Fibrillin
  • Marfan syndrome
  • Microfibrillopathies

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

The molecular genetics of Marfan syndrome and related microfibrillopathies. / Robinson, Peter N.; Godfrey, Maurice.

In: Journal of medical genetics, Vol. 37, No. 1, 18.05.2000, p. 9-25.

Research output: Contribution to journalReview article

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