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Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant form of intestinal polyposis
and colorectal cancer caused by germ-line mutations in the adenomatous polyposis coli
(APC) gene. The term Gardner's syndrome is used to describe extracolonic manifestations,
such as osteomas, skin cysts, congenital hypertrophy of the retinal pigmented epithelium
(CHRPE), and desmoid tumours (aggressive fibromatosis), that are especially prominent
in families with FAP. We postulate that a ciliary dysfunction is the underlying pathogenetic
mechanism of extraintestinal manifestations in patients with FAP. This postulation
is based on the presence of common clinical manifestations (ie, cysts, retinal abnormalities,
and fibrosis) in Gardner's syndrome and cilia-related disorders. Additionally, both
APC and the cilia have degradation of beta-catenin as the common downstream target
in the Wnt-signalling pathway. Mutations in APC causing Gardner's syndrome are clustered
in a region encoding a series of amino-acid repeats responsible for the binding to
beta-catenin. Proofs of principle that beta-catenin could be the key mediator of the
ciliary disorder also rely in the findings that overexpression of beta-catenin induces
polycystic kidney disease, and CHRPE phenotypes in animal models. Other candidates
for the common link between Gardner's syndrome and cilia-related disorders are the
APC-binding proteins: end-binding protein 1 (EB1) and kinesin-family-member 3a (KIF3a),
both of which are ciliary proteins involved in intraflagellar transport. Finally,
pathogenetic similarities between some ciliopathies and extraintestinal tumours in
FAP suggest a cilia defect. Understanding extracolonic manifestations in the context
of FAP as a ciliary disorder might add new therapeutic options for patients with Gardner's
syndrome.