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UNSW
Embryology
DNA- NCBI Genes and
Diseases
Transporters
Introduction
Cystic
Fibrosis
Diastrophic Dysplasia
Long-QT
Syndrome
Menkes' Syndrome
Pendred
Syndrome Adult
Polycystic Kidney Disease Wilson
Disease Zellwegger
Syndrome
About notes
Nervous
Muscle
Immune
Metabolism
Signals
Transport
Introduction
TRANSPORTERS, CHANNELS AND PUMPS that reside in cell
membranes are key to maintaining the right balance of ions
in cells, and are vital for transmitting signals from nerves
to tissues.
The consequences of defects in ion channels and
transporters are diverse, depending on where they are
located and what their cargo is. In the heart,
defects in potassium channels do not allow proper
transmission of electrical impulses, resulting in the
arrythmia seen in long QT syndrome. In the lungs, failure of
a sodium and chloride transporter found in epithelial cells
leads to the congestion of cystic fibrosis, while one of the
most common inherited forms of deafness, Pendred syndrome,
looks to be associated with a defect in a sulphate
transporter.
Link to NCBI page
CYSTIC FIBROSIS (CF) is the most common fatal
genetic disease in the US today. It causes the body
to produce a thick, sticky mucus that clogs the
lungs, leading to infection, and blocks the
pancreas, stopping digestive enzymes from reaching
the intestines where they are required to digest
food. Link to NCBI page
CF is caused by a defective gene, which
codes for a sodium and chloride (salt) transporter
found on the surface of the epithelial cells that
line the lungs and other organs. Several hundred
mutations have been found in this gene, all of
which result in defective transport of sodium and
chloride by epithelial cells. The severity of the
disease symptoms of CF is directly related to the
characteristic effects of the particular
mutation(s) that have been inherited by the
sufferer.
CF research has accelerated sharply
since the discovery of CFTR in 1989. In 1990,
scientists successfully cloned the normal gene and
added it to CF cells in the laboratory, which
corrected the defective sodium chloride transport
mechanism. This technique - gene therapy - was then
tried on a limited number of CF patients. However
this treatment may not be as successful as
originally hoped. Further research will be required
before gene therapy, and other experimental
treatments, prove useful in combating CF.
DIASTROPHIC DYSPLASIA (DTD) is a rare growth disorder in
which patients are usually short, have club feet and have
malformed hands and joints. Although found in all
populations, it is particularly prevalent in Finland.
The gene whose mutation results in DTD maps to
chromosome 5 and encodes a novel sulfate transporter. This
ties in with the observation of unusual concentrations of
sulfate in various tissues of DTD patients. Sulfate is
important for skeletal joints because cartilage - the
shock-absorber of joints - requires sulfur during its
manufacture. Adding sulfur increases the negative charge
within cartilage, which contributes to its shock-absorbing
properties.
A great deal of further research must be done
before this condition is fully understood and effective
therapies are developed.
Link to NCBI page
LONG-QT SYNDROME (LQTS) results from structural
abnormalities in the potassium channels of the heart, which
predispose affected persons to an accelerated heart rhythm
(arrhythmia). This can lead to sudden loss of consciousness
and may cause sudden cardiac death in teenagers and young
adults who are faced with stressors ranging from exercise to
loud sounds.
LQTS is usually inherited as an autosomal
dominant trait. In the case of LQT1, which has been mapped
to chromosome 11, mutations lead to serious structural
defects in the person's cardiac potassium channels that do
not allow proper transmission of the electrical impulses
throughout the heart. There also appear to be other genes,
tentatively located on chromosomes 3, 6 and 11 whose mutated
products may contribute to, or cause, LQT syndrome.
Beta blockers are used to treat the symptoms of
the disease, and appear to be effective in some symptomatic
patients. However, common sense therapies such as avoiding
strenuous physical exercise and other stressors are also
effective. Research on how the genes discussed above
interact with each other should encourage the development of
new treatments for long-QT syndrome.
Link to NCBI page
MENKES' SYNDROME is an inborn error of metabolism that
markedly decreases the cells' ability to absorb copper. The
disorder causes severe cerebral degeneration and arterial
changes, resulting in death in infancy. The disease can
often be diagnosed by looking at a victim's hair, which
appears to be both whitish and kinked when viewed under a
microscope.
Menkes' disease is transmitted as an X-linked
recessive trait. Sufferers can not transport copper, which
is needed by enzymes involved in making bone, nerve and
other structures. A number of other diseases, including type
IX Ehlers-Danlos syndrome, may be the result of allelic
mutations (i.e. mutations in the same gene, but having
slightly different symptoms) and it is hoped that research
into these diseases may prove useful in fighting Menkes'
disease.
If administered within the first few months of
life, copper histidinate appears to be effective in
increasing the life expectancy of some patients. However,
this treatment only increases life expectancy from three to
thirteen years of age, so can only be considered a
palliative. A similar condition to Menkes' disease exists in
mice; working with these model organisms will help give
insight into human copper transport mechanisms, so helping
to develop effective treatments for Menkes' sufferers.
Link to NCBI page
PENDRED SYNDROME is an inherited disorder that accounts
for as much as 10% of hereditary deafness. Patients usually
also suffer from thyroid goiter. The recent discovery of the
gene for Pendred syndrome illuminates a disorder that has
confounded scientists for more than a century.
In December of 1997, scientists at NIH's
National Human Genome Research Institute used the physical
map of human chromosome 7 to help identify an altered gene
thought to cause pendred syndrome. The normal gene makes a
protein, called pendrin, that is found at significant levels
only in the thyroid and is closely related to a number of
sulfate transporters. When the gene for this protein is
mutated, the person carrying it will exhibit the symptoms of
Pendred syndrome.
Because goiter is not always found in Pendred
syndrome patients, it is possible that a defective pendrin
gene will turn out to be responsible for some cases of
deafness that had not previously been attributed to this
disorder. The discovery of pendrin should also stimulate new
angles of research into thyroid physiology and the role of
altered sulfur transport in human disease.
Link to NCBI page
ADULT POLYCYSTIC KIDNEY DISEASE
ADULT POLYCYSTIC kidney disease (APKD) is characterized
by large cysts in one or both kidneys and a gradual loss of
normal kidney tissue. The role of the kidneys in the body is
to filter the blood, excreting the end-products of
metabolism in the form of urine and regulating the
concentrations of hydrogen, sodium, potassium, phosphate and
other ions in the extracellular fluid. Patients with APKD
can die from renal failure, or from the consequences of
hypertension (high arterial blood pressure).
In 1994 the European Polycystic Kidney Disease
Consortium isolated a gene from chromosome 16 that was
disrupted in a family with APCD. The protein encoded by the
PKD1 gene is an integral membrane protein involved in
cell-cell interactions and cell-matrix interactions. The
role of PKD1 in the normal cell may be linked to
microtubule-mediated functions, such as the placement of
Na(+), K(+)-ATPase ion pumps in the membrane. Programmed
cell death, or apoptosis, may also be invoked in APKD.
Further clarification of the pathogenesis of the disease
await further research.
The so-called 'cpk mouse' is a well known model
for the human disease. Studying the molecular basis of the
disease in the mouse is expected to provide a better
understanding of the human disease, and is hoped to lead to
more effective therapies.
Link to NCBI page
WILSON'S DISEASE is a rare autosomal recessive disorder
of copper transport, resulting in copper accumulation and
toxicity to the liver and brain. Liver disease is the most
common symptom in children; neurological disease is most
common in young adults. The cornea of the eye can also be
affected: the 'Kayser-Fleischer ring' is a deep
copper-colored ring at the periphery of the cornea, and is
thought to represent copper deposits.
The gene for Wilson's disease (ATP7B) was mapped
to chromosome 13. The sequence of the gene was found to be
similar to sections of the gene defective in Menkes disease,
another disease caused by defects in copper transport. The
similar sequences code for copper-binding regions, which are
part of a transmembrane pump called a P-type ATPase that is
very similar to the Menkes disease protein.
A homolog to the human ATP7B gene has been mapped to mouse chromosome 8, and an authentic model of the human disease in rat is also available (called the Long-Evans Cinnamon [LEC][ rat). These systems will be useful for studying copper transport and liver pathophysiology, and should help in the development of a therapy for Wilson disease.
Link to NCBI page
ZELLWEGER SYNDROME is a rare hereditary disorder affecting infants, and usually results in death. Unusual problems in prenatal development, an enlarged liver, high levels of iron and copper in the blood, and vision disturbances are among the major manifestations of Zellweger syndrome.
The PXR1 gene has been mapped to chromosome
12; mutations in this gene cause Zellweger syndrome. The
PXR1 gene product is a receptor found on the surface of
peroxisomes - microbodies found in animal cells, especially
liver, kidney and brain cells. The function of peroxisomes
is not fully understood, although the enzymes they contain
carry out a number of metabolically important reactions. The
PXR1 receptor is vital for the import of these enzymes into
the peroxisomes: without it functioning properly, the
peroxisomes can not use the enzymes to carry out their
important functions, such as cellular lipid metabolism and
metabolic oxidations.
There is a yeast homolog to human PXR1, which
should allow powerful molecular genetic techniques to be
used in the investigation of the normal role of peroxisomes
in cells, as well as the molecular events that occur in
disease states.
Link to NCBI page
About Notes
These notes are derived from the NCBI WWW pages Genes and Disease. They are included here for computers without internet access and for educational purposes only. Where possible use the WWW link at the bottom of each section to see the original pages which include images and Links to other resources.