Billy A. Watson and Kerby C. Oberg
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Smith-Lemli-Opitz syndrome (SLOS), for example, is a human metabolic
disorder caused by a mutation in the 7-dehydrocholesterol reductase (7-
DHCR) enzyme, leading to an inborn error of cholesterol biosynthesis. SLOS
is characterized by dysmorphogenesis of multiple organs including the limb.
Noting that cholesterol interacts with hedgehog proteins and modulates their
activity, Porter et al., postulated that there may be defective modification of
the hedgehog proteins and perhaps other similarly processed proteins in SLOS
(Porter et al., 1996).
In terms of limb phenotype, patients present with shortened limbs,
postaxial polydactyly and proximally placed thumbs. Using an in vivo rat
model for cholesterol deficiency, Gofflot et al., then chemically blocked
cholesterol biosynthesis and were able to induce patterns of the autopod
consistent with SLOS patients. Via in situ hybridization, they were also able to
show modifications in downstream targets of Sonic and Indian hedgehog
signaling thereby indicating that cholesterol plays a pivotal role in limb
morphogenesis (Gofflot et al., 2003).
Apart from the apparent role of cholesterol in cell structure and signaling
that could account for the SLOS phenotype, some of the pathologic
characteristics may also be due to accumulation of cholesterol precursors
(Merkens et al., 2004). Currently, dietary cholesterol is being considered as a
therapeutic agent for SLOS (Elias et al., 1997; Irons et al., 1997; Nwokoro and
Mulvihill, 1997) as reports show that dietary cholesterol not only stably
increases plasma cholesterol levels but also decreases plasma concentrations
of the potentially toxic cholesterol precursors through a feedback inhibition
mechanism (Pappu et al., 2002; Merkens et al., 2004). Animal studies in
pregnant rats fed an inhibitor of the enzyme defective in SLOS, and
supplemented with cholesterol, suggest that there may be some benefit to
prenatal therapy (Barbu et al., 1988).
A number of the targeted disruptions have already been discussed above;
however, there are about 1200 different genes associated with just over 500
OMT related phenotypes (for review see OMIM, http://www.ncbi.
nlm.nih.gov/omim; or CulaPhen, Reference in process).
Many of these genetic disorders occur as spontaneous mutations but many
are inherited. For example, advanced age of parents has been linked to
chromosomal abnormalities in their offspring. In Western Australia, the
reported prevalence of congenital hand anomalies increased with maternal age.
Mothers older than 40 years were found to be twice as likely as mothers
younger than 30 years to have a child with a hand deformity (Giele et al.,
2001). Advanced paternal age is also associated with a higher risk for