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The Marfan syndrome
(MFS) (OMIM 154700) is one of the original connective tissue disorders
described by McKusick and colleagues. Its cardinal manifestations are aortic
dilatation and dissection, dislocation of the lenses and overgrowth of long
bones caused by over 600 mutations in the gene encoding fibrillin-1 (FBN1).
Most evidence has suggested that the presence of abnormal fibrillin-1
interferes with the functions of tissues in which it resides. For example, the
disturbance might weaken the ability of the aortic wall to resist hemodynamic
forces, of the suspensory ligaments in the eye to hold the lens in place, or of
the perichondrium to restrain the linear expansion of growing bones. However,
controversy has persisted over the existence of a second MFS gene locus. A
large French family with features of MFS was reported for which linkage was
established not to FBN1 on chromosome 15, but to markers located on
chromosome 3p24.2-p25; the locus was designated MFS2 (OMIM 154705).
Fibrillin-1 is translated from mRNA encoded by FBN1 gene on chromosome 15. (Reprinted with
permission from: Byers PH. J Clin Invest.2004;114:161-63 Copyright ©2004 Am Soc C
linial Investigation.)
Mizuguchi et al evaluated a child with MFS and a complex de
novo chromosome rearrangement that included a breakpoint at the MFS2
locus at 3p24.2-p25. The gene encoding the TGF-ß receptor 2 (TGFBR2) was
disrupted and a point mutation disturbed its splicing in affected members of
the French family. They identified 3 additional missense TGFBR2 mutations
from analysis of 3 French families and 10 unrelated Japanese patients with MFS
who had no mutation or linkage to FBN1, and demonstrated that several of
the MFS mutations resulted in loss of receptor function.
TGF-ß receptors belong to the serine-threonine kinase
family of cell surface receptors. When activated, they recruit and
phosphorylate serine and threonine residues on cytoplasmic proteins that propagate
TGF-ß signals to downstream pathways in cells. TGF-ßs regulate many cellular
processes including proliferation, cell cycle arrest, apoptosis,
differentiation and formation of extracellular matrix. Type II receptors are
thought to mediate growth inhibitory signals, and TGFBR2 is considered
to be a tumor suppressor gene.
Byers described fibrillin-1 binding to so-called latent
TGF-ß binding proteins (LBPs). These bind to inactive, latent TGF-ßs. In this
way, fibrillin-1 can influence the extracellular availability of active TGF-ß.
In MFS, the model suggests that mutations reduce the amount of fibrillin-1 in
the matrix. The consequence is diminished sequestration of LBP-bound TGF-ß and
a relative increase in the abundance of active TGF-ß in the matrix. In
TGF-ß-responsive tissues, this results in exaggeration of processes that are
regulated by TGF-ß, such as growth (Figure). Support for this idea comes from
work recently published by Neptune et al, in which it is demonstrated that
emphysematous changes in the lungs of fibrillin-1 null mice could be partially
ameliorated by antibodies that block TGF-ß function.
Mizuguchi T, Collod-Beroud G, Akiyama T, et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet. 2004;36:855-860.
Byers PH. Determination of the molecular basis of Marfan syndrome: a growth industry. J Clin Invest. 2004;114:161-163.
Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407-411.
Editor’s Comment: Taken together, these 3 papers strongly implicate
TGF-ß playing a role in the pathogenesis of MFS. As suggested by these groups,
the findings open up many new possibilities for treatment that focuses on
excessive TGF-ß signaling as the target. These papers also highlight somewhat
of a renaissance in thinking about extracellular matrix and its components;
they are not just static structural proteins, but dynamic elements that play
important functional roles in development and disease.
William A. Horton, MD
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Current GGH - Vol. 24 No. 1
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