The Questions of Developmental Biology

The Nature of Human Syndromes
As we have seen, human infants are sometimes born with congenital malformations that
range from life-threatening to relatively benign. Congenital means "at birth," and this term
reflects the fact that these malformations are errors of development. Often these malformations
are linked into syndromes (see Chapter 1).
Pleiotropy
The production of several effects by one gene is called pleiotropy. For instance, in
humans, heterozygosity for MITF causes a condition called Waardenburg syndrome type 2, as we
saw in Chapter 4 (Figure 4.25). This syndrome involves iris defects, pigmentation abnormalities,
deafness, and inability to produce the normal number of mast cells (a type of blood cell). The skin
pigment, the iris of the eye, the inner ear tissue, and the mast cells of the blood are not related to
one another in such a way that the absence of one would produce the absence of the others.
Rather, all four parts of the body independently use the MITF protein as a transcription factor.
This type of pleiotropy has been called mosaic pleiotropy, because the affected organ systems
are separately affected by the abnormal gene function.
While the eye pigment, body pigment, and mast cell features of Waardenburg syndrome
type 2 are separate events, other parts of the syndrome are not. For instance, the failure of MITF
expression in the pigmented retina prevents this structure from fully differentiating. This in turn
causes a malformation of the choroid fissure of the eye, resulting in the drainage of vitreous
humor fluid. Without this fluid, the eye fails to enlarge (hence the name microphthalmia, which
means "small eye"). This phenomenon, in which
several developing tissues are affected by the
mutation even though they do not express the
mutated gene, is called relational pleiotropy (see
Gruneberg 1938).
Genetic heterogeneity
Another important feature of syndromes is
that mutations in different genes can produce the
same phenotype. If the genes are part of the same
signal transduction pathway, a mutation in any of
them can give a similar result. The phenomenon
whereby mutations in different genes produce
similar phenotypes is called genetic heterogeneity.
For example, cyclopia can be produced by mutations
in the Sonic hedgehog gene or by mutations in
cholesterol synthesis genes. Since they are in the
same pathway, mutations in one gene generate a
phenotype similar or identical to mutations in the
other genes. Similarly, as we saw above, mutations
in the stem cell factor (Steel) gene produce a
syndrome resembling that produced by mutations in
the gene for its receptor, the Kit protein (White).
Since mutations of either of these genes prevent Mitf
from being activated, they produce a phenotype