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Embryology
DNA- NCBI Genes and
Diseases The
Nervous System
Introduction
Amyotrophic
Lateral Sclerosis Alzheimer
Disease Charcot-Marie-Tooth
Essential
Tremor Fragile
X Syndrome Huntington
Disease Niemann-Pick
Parkinson
Disease
Spinocerebellar Atrophy
Williams
Syndrome About
Notes
Nervous
Muscle
Immune
Metabolism
Signals
Transport
Introduction
THE BRAIN and nervous system form an intricate network of
electrical signals that are responsible for coordinating
muscles, the senses, speech, memories, thought and
emotion.
Several diseases that directly affect the
nervous system have a genetic component: some are due to a
mutation in a single gene, others are proving to have a more
complex mode of inheritance. As our understanding of the
pathogenesis of neurodegenerative disorders deepens, common
themes begin to emerge: Alzheimer brain plaques and the
inclusion bodies found in Parkinson disease contain at least
one common component, while Huntington disease, fragile X
syndrome and spinocerebellar atrophy are all 'dynamic
mutation' diseases in which there is an expansion of a DNA
repeat sequence. Apoptosis is emerging as one of the
molecular mechanisms invoked in several neurodegenerative
diseases, as are other, specific, intracellular signaling
events. The biosynthesis of myelin and the regulation of
cholesterol traffic also figure in Charcot-Marie-Tooth and
Neimann-Pick disease, respectively.
Link to NCBI page
AMYOTROPHIC LATERAL SCLEROSIS (ALS) is a neurological
disorder characterized by progressive degeneration of motor
neuron cells in the spinal cord and brain, which ultimately
results in paralysis and death. The disease takes its
less-scientific name from Lou Gehrig, a baseball player with
the New York Yankees in the late 1920s and 1930s, who was
forced to retire in 1939 as a result of the loss of motor
control caused by the disease.
In 1991, a team of researchers linked familial
ALS to chromosome 21. Two years later, the SOD1 gene was
identified as being associated with many cases of familial
ALS. The enzyme coded for by SOD1 carries out a very
important function in cells: it removes dangerous superoxide
radicals by converting them into non-harmful substances.
Defects in the action of this enzyme mean that the
superoxide radicals attack cells from the inside, causing
their death. Several different mutations in this enzyme all
result in ALS, making the exact molecular cause of the
disease difficult to ascertain.
Recent research has suggested that treatment
with drugs called anti-oxidants may benefit ALS patients.
However, since the molecular genetics of the disease are
still unclear, a significant amount of research is still
required to design other promising treatments for ALS.
Link to NCBI page
ALZHEIMER DISEASE (AD) is the fourth leading
cause of death in adults. The incidence of the
disease rises steeply with age. AD is twice as
common in women than in men, although ex-president
Ronald Reagan is a well known disease sufferer.
Some of the most frequently observed symptoms of
the disease include a progressive inability to
remember facts and events and, later, to recognize
friends and family. Link to NCBI page
AD tends to run in families: currently,
mutations in four genes, situated on chromosomes 1,
14, 19 and 21, are believed to play a role in the
disease. The best-characterized of these are PS1
(or AD3) on chromosome 14 and PS2 (or AD4) on
chromosome 1. The formation of lesions made of
fragmented brain cells surrounded by amyloid-family
proteins are characteristic of the disease.
Interestingly, these lesions and their associated
proteins are closely related to similar structures
found in Down's Syndrome. Tangles of filaments
largely made up of a protein associated with the
cytoskeleton have also been observed in samples
taken from Alzheimer brain tissue.
Currently, scientists are studying the
interrelationship between the various gene loci
(particularly the mutation on chromosome 21), and
how environmental factors could effect a person's
susceptibility to AD. Recently, use of a mouse
model of the disease identified an enzyme that may
be responsible for the increase in amyloid
production characteristic of AD. If a way to
regulate this enzyme could be found, then AD may be
slowed or halted in some people.
CHARCOT-MARIE-TOOTH disease (CMT) disease is named after
its three discoverers, who first noted the disease around
the turn of the century. It is the most common inherited
peripheral neuropathy in the world, characterized by a
slowly progressive degeneration of the muscles in the foot,
lower leg, hand and forearm, and a mild loss of sensation in
the limbs, fingers and toes. Full expression of CMT's
clinical symptoms generally occurs by age 30. CMT is not a
fatal disease, however, and the disorder does not affect
normal life expectancy.
CMT is a genetically heterogeneous disorder, in
which mutations in different genes can produce the same
clinical symptoms. In CMT, there are not only different
genes but different patterns of inheritance. One of the most
common forms of CMT is Type 1A. The gene for Type 1A CMT
maps to chromosome 17 and is thought to code for a protein
(PMP22) involved in coating peripheral nerves with myelin, a
fatty sheath that is important for their conductance. Other
types of CMT include Type 1B, autosomal-recessive and
X-linked.
The same proteins involved in the Type 1A and
Type 1B CMT are also involved in a disease called
Dejerine-Sottas syndrome (DSS), in which similar clinical
symptoms are presented, but they are more severe. Research
into under standing the pathogenesis of CMT, through the use
of animal models for the disease, should also give insight
into DSS, and may lead to therapies for both diseases.
Link to NCBI page
TREMOR , or uncontrollable shaking, is a common symptom
of neurological disorders such as Parkinson disease, head
trauma and stroke. However, many people with tremor have
what is called idiopathic or essential tremor. In these
cases, which number 3-4 million people in the US, the tremor
itself is the only symptom of the disorder. While essential
tremor may involve other parts of the body, the hands and
head are most often affected.
In more than half of cases, essential tremor is
inherited as an autosomal dominant trait, which means that
children of an affected individual will have a 50 percent
chance of also developing the disorder. In 1997, the ETM1
gene (also called FET1) was mapped to chromosome 3 in a
study of Icelandic families, while another gene, called
ETM2, was mapped to chromosome 2 in a large American family
of Czech descent. That two genes for essential tremor have
been found on two different chromosomes demonstrates that
mutations in a variety of genes may lead to essential
tremor.
While the mainstays of treatment are drugs such
as propranolol and primidone, alternative drugs and surgical
treatments are also available. Further understanding of the
molecular mechanism behind the disease awaits the discovery
and cloning of an essential tremor gene.
Link to NCBI page
FRAGILE X SYNDROME is the most common inherited form of
mental retardation currently known. Fragile X syndrome is a
defect in the X chromosome and its effects are seen more
frequently, and with greater severity, in males than
females.
In normal individuals, the FMR1 gene is
transmitted stably from parent to child. However, in Fragile
X individuals, there is a mutation in one end of the gene
(the 5' untranslated region), consisting of an amplification
of a CGG repeat. Patients with fragile X syndrome have 200
or more copies of the CGG motif. The huge expansion of this
repeat means that the FMR1 gene is not expressed, so no FMR1
protein is made. Although the exact function of FMR1 protein
in the cell is unclear, it is known that it binds RNA.
A similar nucleotide repeat expansion is seen in
other diseases, such as Huntington disease. Research in mice
has proven helpful in elucidating some of the mechanisms
that cause the instability of this gene. Our methods for
identifying carriers of Fragile X syndrome have also
improved, and further research will help people carrying
'premutations' to avoid having children who have a larger
expansion (ie more CGG repeats) in FMR1, and therefore
suffer from fragile X syndrome.
Link to NCBI page
HUNTINGTON DISEASE (HD) is an inherited, degenerative
neurological disease that leads to dementia. About 30,000
Americans have HD and about 150,000 more are at risk of
inheriting the disease from a parent.
The HD gene, whose mutation results in
Huntington disease, was mapped to chromosome 4 in 1983 and
cloned in 1993. The mutation is a characteristic expansion
of a nucleotide triplet repeat in the DNA that codes for the
protein huntingtin. The number of repeated triplets - CAG
(cytosine, adenine, guanine) - increases with the age of the
patient. Since people who have those repeats always suffer
from Huntington disease, it suggests that the mutation
causes a gain-of-function, in which the mRNA or protein
takes on a new property or is expressed inappropriately.
With the discovery of the HD gene, a new
predictive test was developed that allows those at risk to
find out whether or not they will develop the disease.
Animal models have also been developed, and we know that
mice have a gene that is similar to the human HD gene.
Research on understanding the mechanism that causes the
triplet repeat to increase is ongoing, since its discovery
could be critical to the development of an effective
treatment for this and other similar diseases.
Link to NCBI page
In 1914, GERMAN PEDIATRICIAN Albert Niemann described a
young child with brain and nervous system impairment. Later,
in the 1920's, Luddwick Pick studied tissues after the death
of such children and provided evidence of a new disorder,
distinct from those storage disorders previously
described.
Today, there are three separate diseases that
carry the name Niemann-Pick: Type A is the acute infantile
form, Type B is a less common, chronic, non-neurological
form, while Type C is a biochemically and genetically
distinct form of the disease. Recently, the major locus
responsible for Niemann-Pick type C (NP-C) was cloned from
chromosome 18, and found to be similar to proteins that play
a role in cholesterol homeostasis.
Usually, cellular cholesterol is imported into
lysosomes - 'bags of enzymes' in the cell - for processing,
after which it is released. Cells taken from NP-C patients
have been shown to be defective in releasing cholesterol
from lysosomes. This leads to an excessive build-up of
cholesterol inside lysosomes, causing processing errors.
NPC1 was found to have known sterol-sensing regions similar
to those in other proteins, which suggests it plays a role
in regulating cholesterol traffic.
Link to NCBI page
PARKINSON DISEASE, first described by James Parkinson in
1817, is a growing national problem, with more than half a
million Americans affected at any one time. Most people are
over 50 years old when the disease appears, although it can
occur in younger patients. It is a neuodegenerative disease
that manifests as a tremor, muscular stiffness and
difficulty with balance and walking. A classic pathological
feature of the disease is the presence of an inclusion body,
called the Lewy body, in many regions of the brain.
Until relatively recently, Parkinson disease was
not though to be heritable, and research was primarily
focused on environmental risk factors such as viral
infection or neurotoxins. However, a positive family history
was gradually perceived to be a risk factor, a view that was
confirmed last year when a candidate gene for some cases of
Parkinson disease was mapped to chromosome 4. Mutations in
this gene have now been linked to several Parkinson disease
families. The product of this gene, a protein called
alpha-synuclein, is a familiar culprit: a fragment of it is
a known constituent of Alzheimer disease plaques.
Since alpha-synuclein fragments are implicated
in both Parkinson and Alzheimer diseases, there may be
shared pathogenic mechanisms between the two, therefore
research into one disease may aid understanding of the
other. Further avenues for research are also being suggested
by cross-species comparisons assisted by database searching.
Among others, rats, cows and zebra finches all possess
alpha-synuclein; in the rat they play a role in the sense of
smell, while in the zebra finch it is thought to be involved
in the process of song learning. Further work to elucidate
the function of alpha-synuclein in humans, and therefore
clues as to the pathology of Parkinson disease, should be
assisted by studying these other species. Link to NCBI
page
PERSONS WITH spinocerebellar atrophy, of which there are
several types, experience a degeneration of the spinal cord
and the cerebellum, the small fissured mass at the base of
the brain, behind the brain stem. The cerebellum is
concerned with coordination of movements, so atrophy or
"wasting away" of this critical control center results in a
loss of muscle coordination. Atrophy in the spine can bring
spasticity.
The basic defect in all types of spinocerebellar
atrophy is a an expansion of a CAG triplet repeat. In this
way, it is similar to fragile-X syndrome, Huntington disease
and myotonic dystrophy, all of which exhibit a triplet
repeat expansion of a gene. In the case of spinocerebellar
atrophy I, the gene is SCA1, found on chromosome 6. The
protein product of the gene - called ataxin-1 - varies in
size, depending on the size of the CAG triplet repeat.
A homolog of human ataxin-1 has been found in mice, where it is found on chromosome 13 instead of chromosome 6.. The two proteins are highly similar, except that in the mouse, the poly-glutamine tract (coded for by the CAG repeat ) is missing, suggesting that it is not essential for normal function in mice.
Link to NCBI page
WILLIAMS SYNDROME is a rare congenital disorder characterized by physical and development problems. Common features include characteristic "elfin-like" facial features, heart and blood vessel problems, irritability during infancy, dental and kidney abnormalities, hyperacusis (sensitive hearing) and musculoskeletal problems. Although individuals with Williams syndrome may show competence in areas such as language, music and interpersonal relations, their IQs are usually low.
In Williams syndrome individuals, both the
gene for elastin and an enzyme called LIM kinase are
deleted. Both genes map to the same small area on chromosome
7. In normal cells, elastin is a key component of connective
tissue, conferring its elastic properties. Mutation or
deletion of elastin lead to the vascular disease observed in
Williams syndrome. On the other hand, LIM kinase is strongly
expressed in the brain, and deletion of LIM kinase is
thought to account for the impaired visuospatial
constructive cognition in Williams syndrome.
Williams syndrome is a contigious disease,
meaning that the deletion of this section of chromosome 7
may involve several more genes. Further study will be
required to round up all the genes deleted in this disease.
The remarkable musical and verbal abilities of individuals
with Williams syndrome, and their tendency to be very
sociable, has lead to the suggestion that children with
Williams syndrome were an inspiration for folktales and
legends, as the 'wee, magical people' were often musicians
and storytellers.
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 many Links to other resources.