FIRST GENE DIRECTLY LINKED TO WILLIAMS
SYNDROME
A Scientific Explanation For WS Families
(Written in 1993)
by
*Howard M. Lenhoff, Executive Vice President
Williams Syndrome Foundation, and
Professor of Developmental and Cell Biology
University of California, Irvine
***
The discovery - a loss of the gene for elastin through a
microdeletion
of chromosome seven:
Dr. Colleen Morris and her collaborators have shown
conclusively that nearly all Williams people tested lack
the gene for
elastin in one of their two chromosomes called "chromosome
Number 7,"
whereas the normal parents possess both copies of the gene.
Every
non-Williams person has two chromosome Number 7s, having
received one
from each parent. Technically speaking, the absence of a
gene or of any
small segment of a chromosome is called a microdeletion.
One of the
genes removed in the microdeletion of chromosome Number 7
in WS
individuals is the gene controlling the synthesis of
elastin, a protein
important in the functioning of contractile tissues, such
as those found
in the heart and arteries (see related questions and
answers about
elastin).
***
Is a microdeletion a mutation? No, not in the strict sense.
A gene is
the particular segment of a long chain of DNA
(deoxyribonucleic acid)
which provides information for the cell to make a specific
protein, such
as hemoglobin or elastin. The DNA chain is made up of a
specific
arrangement of four smaller molecules, called A, G, T, and
C for short,
that are linked together. A mutation occurs when some
foreign agent,
such as radiation, causes a permanent change in one of the
A, G, T, or C
molecules. In contrast, a microdeletion occurs when a gene
or a small
number of genes are removed from a chromosome.
***
Where does the microdeletion originate? The microdeletion
must originate
in either the egg or sperm provided by the parents which
unite to form
the fertilized egg giving rise to the Williams syndrome
child. We can
conclude that nothing could have happened during the
gestation of the
Williams child that could have contributed to the
establishment of that
microdeletion. Williams syndrome is established at
conception, and not
thereafter.
***
What are the chances of a family having two children with
Williams
syndrome? Extremely rare, except in the case of identical
twins.
***
What are the chances of a brother or sister of a Williams
individual
having a child with Williams syndrome? Also extremely rare,
with no
greater a chance than individuals from the general
population.
***
Can the microdeletion be passed on from a Williams syndrome
individual
who parents a child? Yes. There is a 50/50 chance that a
Williams parent
can pass on the chromosome with the microdeletion to its
offspring
because the Williams syndrome parent has two chromosomes
Number 7, one
with the microdeletion, and one without it. Either one of
the two
chromosomes of the Williams parent will appear in the
gamete (i.e. egg
or sperm) which eventually forms the child. If it is the
chromosome with
the microdeletion, then the child will also be a Williams
child. If it
is the chromosome without the microdeletion, then the child
will not be
a Williams child. It is strictly a matter of chance whether
or not the
Williams parent passes on the chromosome 7 with the
microdeletion to her
or his offspring.
***
Will this discovery allow for the early diagnosis of
Williams syndrome?
Yes. Because it is possible to mark with a fluorescent dye
the complete
Number 7 chromosome (the one without the microdeletion) and
not the
defective Number 7 chromosome (the one having the
microdeletion), it is
possible to analyze the cells of the early embryo removed
by the
processes of amniocentesis or chorionic villi analysis, or
to analyze
cells of a WS child at any age. Perhaps the most useful
aspect of such
early diagnoses is that it will now be possible to use this
chromosomal
test as a near conclusive diagnostic indicator of WS when
evaluations of
other characteristics of the syndrome are in doubt.
Nonetheless, there
still remains the possibility that there will be a small
percentage of
individuals with Williams syndrome who will not show this
microdeletion.
***
Does the discovery of the microdeletion of the elastin gene
in Williams
syndrome individuals explain all of the characteristics of
Williams
syndrome? Not completely. The microdeletion of the elastin
gene can help
explain the: facial features; low voice; diverticulosis
(formation of a
sac or pouch) of the bladder and colon; and heart, hernia,
and joint
problems present in Williams syndrome individuals. Why?
Because
sufficient amounts of the protein elastin are needed for
normal
functioning of the heart, aorta, and other contractile
tissues and
organs. It is particularly interesting to note that WS
individuals both
with and without heart problems show the microdeletion of
the elastin
gene.
***
What are some questions that need to be answered? It is not
clear at
this time, for example, how the absence of an elastin gene
would lead to
hypercalcaemia, mental retardation, musical ability, and
other features
of Williams syndrome. One possibility which needs to be
explored
suggests that the gene or genes affecting those other
traits may be
close to the elastin gene, and because of the closeness
also may be
eliminated in the microdeletion. It is also possible that
the
microdeletions in chromosome Number 7 of WS individuals may
differ in
size, with varying numbers of other genes missing, thereby
accounting
for individuals who have some of the WS symptoms, but who
are still hard
to diagnose with certainty. Such possible variation in the
size of the
microdeletion may account for some of the variability in
the symptoms of
WS seen in different individuals.
---
Thus, although we are now much closer to understanding the
genetic basis
of Williams syndrome, there is still additional genetic
research that
needs to be done. The path, however, now looks shorter and
clearer
because of the pioneering work of Dr. Morris and her
colleagues.
***
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