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Embryology
DNA- NCBI Genes and
Diseases
Metabolism
Introduction
Adrenoleukodystrophy
Atherosclerosis
Diabetes
Gaucher
Gyrate
Atrophy Obesity
PhenylketonuriaParoxysmal
Nocturnal Hemoglobinuria
Refsum
disease About
Notes
Nervous
Muscle
Immune
Metabolism
Signals
Transport
ADRENOLEUKODYSTROPHY (ALD) is a rare, inherited
metabolic disorder that afflicts the young boy
Lorenzo Odone, whose story is told in the 1993 film
'Lorenzo's oil'. In this disease the fatty covering
(myelin sheath) on nerve fibers in the brain is
lost, and the adrenal gland degenerates, leading to
progressive neurological disability and death. People with ALD accumulate high
levels of saturated, very long chain fatty acids in
their brain and adrenal cortex because the fatty
acids are not broken down by an enzyme in the
normal manner. So, when the ALD gene was discovered
in 1993, it was a surprise that the corresponding
protein was in fact a member of a family of
transporter proteins, not an enzyme. It is still a
mystery as to how the transporter effects the
function the fatty acid enzyme, and for that
matter, how high levels of very long chain fatty
acids cause the loss of myelin on nerve fibers.
More recently, all the transporters
related to ALD protein have been found in the yeast
Saccharomyces cerevisiae, and a mouse model for the
human disease has been developed. These and other
molecular biology approaches should further our
understanding of ALD and hasten our progress
towards effective therapies. Link to NCBI page
ATHEROSCLEROSIS is a disease that can affect people at
any age, although it usually doesn't pose a threat until
people reach their forties or fifties. It is characterized
by a narrowing of the arteries caused by cholesterol-rich
plaques of immune-system cells. Key risk factors for
atherosclerosis, which can be genetic and/or environmental,
include: elevated levels of cholesterol and triglyceride in
the blood, high blood pressure and cigarette smoke.
A protein called apolipoprotein E, which can
exist in several different forms, is coded for by a gene
found on chromosome 19. It is important for removing excess
cholesterol from the blood, and does so by carrying
cholesterol to receptors on the surface of liver cells.
Defects in apolipoprotein E sometimes result in its
inability to bind to the receptors, which leads to an
increase a person's blood cholesterol, and consequently
their risk of atherosclerosis.
Currently, a debate is raging over how the various mutated forms of apolipoprotein E effect the body. As a result, many of the treatments proposed remain in their experimental phase. While mice are proving useful for modeling the human disease, a great deal of research is still required before we can fully understand the mechanisms that regulate the levels of lipoproteins - like apolipoprotein E - in the blood.
Link to NCBI page
DIABETES is a chronic metabolic disorder that adversely
affects the body's ability to manufacture and use insulin, a
hormone necessary for the conversion of food into energy.
The disease greatly increases the risk of blindness, heart
disease, kidney failure, neurological disease and other
conditions for the approximately 16 million Americans who
are affected by it. Type I, or juvenile onset diabetes, is
the more severe form of the illness.
Type I diabetes is what is known as a 'complex
trait', which means that mutations in several genes likely
contribute to the disease. For example, it is now known that
the insulin-dependent diabetes mellitus (IDDM1) locus on
chromosome 6 may harbor at least one susceptibility gene for
Type I diabetes. Exactly how a mutation at this locus adds
to patient risk is not clear, although a gene maps to the
region of chromosome 6 that also has genes for antigens (the
molecules that normally tell the immune system not to attack
itself). In Type I diabetes, the body's immune system mounts
an immunological assault on its own insulin and the
pancreatic cells that manufacture it. However, the mechanism
of how this happens is not yet understood.
About 10 loci in the human genome have now been
found that seem to confer susceptibility to Type I diabetes.
Among these are (1) a gene at the locus IDDM2 on chromosome
11 and (2) the gene for glucokinase (GCK), an enzyme that is
key to glucose metabolism which helps modulate insulin
secretion, on chromosome 7.
Conscientious patient care and daily insulin
dosages can keep patients comparatively healthy. But in
order to prevent the immunoresponses that often cause
diabetes, we will need to experiment further with mouse
models of the disease, and advance our understanding of how
genes on other chromosomes might add to a patient's risk of
diabetes.
Link to NCBI page
GAUCHER (pronounced "go-SHAY") disease is an inherited
illness caused by a gene mutation. Normally, this gene is
responsible for an enzyme called glucocerebrosidase that the
body needs to break down a particular kind of fat called
glucocerebroside. In people with Gaucher disease, the body
is not able to properly produce this enzyme and the fat
cannot be broken down. It then accumulates, mostly in the
liver, spleen and bone marrow. Gaucher disease can result in
pain, fatigue, jaundice, bone damage, anemia and even
death.
Gaucher disease is considerably more common in
the descendants of Jewish people from eastern Europe
(Ashkenazi), although individuals from any ethnic group may
be affected. Among the Ashkenazi Jewish population, Gaucher
disease is the most common genetic disorder, with an
incidence of approximately 1 in 450 persons. In the general
public, Gaucher disease affects approximately 1 in 100,000
persons. According to the National Gaucher Foundation, 2,500
Americans suffer from Gaucher disease.
In 1991, enzyme replacement therapy became
available as the first effective treatment for Gaucher
disease. The treatment consists of a modified form of the
glucocerebrosidase enzyme given intravenously. Performed on
an outpatient basis, the treatment takes about 1-2 hours and
is given every 2 weeks. Enzyme replacement therapy can stop
and often reverse the symptoms of Gaucher disease, allowing
patients to enjoy a better quality of life.
Link to NCBI page
PEOPLE SUFFERING FROM gyrate atrophy of the choroid (the
thin coating of the eye) and retina face a progressive loss
of vision, with total blindness usually occurring between
the ages of 40 and 60. The disease is an inborn error of
metabolism.
The gene whose mutation causes gyrate atrophy is
found on chromosome 10, and encodes an enzyme called
ornithine ketoacid aminotransferase (OAT). Different
inherited mutations in OAT cause differences in the severity
of symptoms of the disease. OAT converts the amino acid
ornithine from the urea cycle ultimately into glutamate. In
gyrate atrophy, where OAT function is affected, there is an
increase in plasma levels of ornithine.
It is already known that reduction of the amino
acid arginine in the diet has a salutary effect on most
patients. Current lines of research into the disease
include: (1) investigating how variant mutations of the
alleles (versions of the gene inherited) interact in order
to cause the differing symptoms of the disease and (2) work
on mouse models of the disease is furthering our
understanding, which is hoped will lead to a true cure.
Link to NCBI page
OBESITY is an excess of body fat that frequently results
in a significant impairment of health. Doctors generally
agree that men with more than 25% body fat and women with
more than 30% are obese. Obesity is a known risk factor for
chronic diseases including heart disease, diabetes, high
blood pressure, stroke and some forms of cancer. Evidence
suggests that obesity has more than one cause: genetic,
environmental, psychological and other factors may all play
a part.
The hormone leptin, produced by adipocytes (fat
cells), was discovered about three years ago in mice.
Subsequently the human Ob gene was mapped to chromosome 7.
Leptin is thought to act as a lipostat: as the amount of fat
stored in adipocytes rises, leptin is released into the
blood and signals to the brain that the body has enough to
eat. However, most overweight people have high levels of
leptin in their bloodstream, indicating that other molecules
also effect feelings of saity and contribute to the
regulation of body weight.
The discovery of leptin has initiated a flurry
of research into the molecular basis of weight control. A
whole network of signals contributes to weight homeostasis,
and other key players are being discovered on an ongoing
basis. Mice have proved to be an extremely useful model for
human obesity, and have helped to begin to unravel the
components that contribute to maintaining body weight. Since
the market for effective weight-reducing therapies is
enormous, drug companies are working alongside basic
scientists to find possible drug targets among the tangle of
molecules that control body weight.
Link to NCBI page
PHENYLKETONURIA (PKU) is an inherited error of metabolism
caused by a deficiency in the enzyme phenylalanine
hydroxylase. Loss of this enzyme results in mental
retardation, organ damage, unusual posture and can, in cases
of maternal PKU, severely compromise pregnancy.
Classical PKU is an autosomal recessive
disorder, caused by mutations in both alleles of the gene
for phenylalanine hydroxylase (PAH), found on chromosome 12.
In the body, phenylalanine hydroxylase converts the amino
acid phenylalanine to tyrosine, another amino acid.
Mutations in both copies of the gene for PAH means that the
enzyme is inactive or is less efficient, and the
concentration of phenylalanine in the body can build up to
toxic levels. In some cases, mutations in PAH will result in
a phenotypically mild form of PKU called
hyperphenylalanemia. Both diseases are the result of a
variety of mutations in the PAH locus; in those cases where
a patient is heterozygous for two mutations of PAH (ie each
copy of the gene has a different mutation), the milder
mutation will predominate.
A form of PKU has been discovered in mice, and
these model organisms are helping us to better understand
the disease, and find treatments against it. With careful
dietary supervision, children born with PKU can lead normal
lives, and mothers who have the disease can produce healthy
children. Link to NCBI page
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
THE DISTINCT and rather peculiar characteristics of
paroxysmal nocturnal hemoglobinuria (PNH) have puzzled
hematologists for more than a century. PNH is characterized
by a decreased number of red blood cells (anemia), and the
presence of blood in the urine (hemoglobinuria) and plasma
(hemoglobinemia), which is evident after sleeping. PNH is
associated with a high risk of major thrombotic events, most
commonly thrombosis of large intra-abdominal veins. Most
patients who die of their disease die of thrombosis.
PNH blood cells are deficient in an enzyme known
as PIG-A, which is required for the biosynthesis of cellular
anchors. Proteins that are partly on the outside of cells
are often attached to the cell membrane by a
glycosylphosphatidylinositol (GPI) anchor, and PIG-A is
required for the synthesis of a key anchor component. If
PIG-A is defective, surface proteins that protect the cell
from destructive components in the blood (complement) are
not anchored and therefore absent, so the blood cells are
broken down.
The PIG-A gene is found on the X chromosome.
Although not an inherited disease, PNH is a genetic
disorder, known as an acquired genetic disorder. The
affected blood cell clone passes the altered PIG-A to all
its descendants--red cells, leukocytes (including
lymphocytes), and platelets. The proportion of abnormal red
blood cells in the blood determines the severity of the
disease.
Link to NCBI page
REFSUM DISEASE is a rare disorder of lipid metabolism
that is inherited as a recessive trait. Symptoms may include
a degenerative nerve disease (peripheral neuropathy),
failure of muscle coordination (ataxia), retinitis
pigmentosa (a progressive vision disorder), and bone and
skin changes. Refsum disease is characterized by an
accumulation of phytanic acid in the plasma and tissues. is
a derivative of phytol, a component of chlorophyll.
In 1997 the gene for Refsum disease was
identified and mapped to chromosome 10. The protein product
of the gene, PAHX, is an enzyme that is required for the
metabolism of phytanic acid. Refsum disease patients have
impaired PAHX - phytanic acid hydrolase. It is thought that
Refsum disease is a peroxisomal disorder, since human PAHX
contains PTS2 localization sequences, which target it to the
peroxisome.
Our bodies can not synthesize phytanic acid: we
have to obtain all of it from our food. Therefore, prolonged
treatment with a diet deficient in phytanic acid can be
beneficial.
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.